BRPI0614122A2 - quinoline derivative, pharmaceutical composition and use of said compound - Google Patents

Abstract

QUINOLINE DERIVATIVE COMPOUND, PHARMACEUTICAL COMPOSITION AND USE OF SUCH COMPOUND. The present invention relates to novel substituted quinoline derivatives according to general formulas (1a) or (1b): to a pharmaceutically acceptable acid or base addition salt thereof, a quaternary amine thereof, a stereochemically form isomeric form, a tautomeric form thereof, an N-oxide form thereof or a prodrug thereof. The claimed compounds are of use in the treatment of a bacterial disease, particularly diseases caused by pathogenic mycobacteria, such as Mycobacterium tuberculosis, M. bovis, M. avium and M. marinum. Also claimed is a composition comprising a pharmaceutically acceptable carrier and, as an active ingredient, a therapeutically effective amount of the claimed compounds, the use of the claimed compounds or compositions for the manufacture of a medicament for the treatment of bacterial diseases and a process for preparation of the claimed compounds.

Description

Patent Descriptive Report for "Quinoline Compound, Pharmaceutical Composition and Compound Diffused Use".

The present invention relates to novel substituted quinoline derivatives useful in the treatment of bacterial diseases, including, but not limited to, diseases caused by pathogenic mycobacteria, such as Mycobacterium tuberculosis, M. bovis, M. avium and M. marinum.

Background of the Invention

Mycobacterium tuberculosis is the causative agent of tuberculosis (TB), a serious and potentially fatal, widespread infection worldwide. World Health Organization estimates indicate that more than 8 million people get TB each year and 2 million people die of tuberculosis annually. Over the past decade, TB cases have grown by 20% worldwide, higher index in the poorer communities. If these trends continue, the incidence of TB will increase by more than 41% in the next twenty years. Fifty years after the introduction of effective chemotherapy, TB remains after AIDS as the leading infectious cause of mortality in the world. The complication of epidemic TB provides a tendency for multidrug-resistant strains to emerge and deadly symbiosis with HIV. People who are HIV-infected and infected with TB are 30 times more likely to develop activated TB than people who are HIV-negative, and TB is responsible for the death of one in three people with HIV / AIDS worldwide. world.

Approaches to tuberculosis treatment also involve the combination of multiple agents. For example, the regimen recommended by the US Public Health Service is a combination of isoniazid, rifampicin and pyrazinamide for two months, followed by isoniazid and rifam picine for only another four months. These drugs are continued for another seven months in HIV-infected patients. For patients infected with multidrug resistant M. tuberculosis strains, certain agents such as ethambutol, streptomycin, kanamycin, ca-preomycin, etionamide, cycloserine, ciprofoxacin and ofloxacin are added to combinatorial therapies. There are no single agents that are effective in the clinical treatment of tuberculosis or any combination of agents that offer the possibility of therapy of less than six months duration.

Thus, there is a great medical need for new drugs that improve the current treatment, enabling regimens that facilitate the patient and provide acceptance. Shorter regimes and also those that require less supervision are considered as the best way to achieve this goal. Most of the benefit of treatment is achieved within the first 2 months during the bactericidal phase, when four drugs are given together; Cargabacterial is markedly reduced and patients become non-infectious. Continuation from the fourth to sixth month, or sterilization phase, is necessary to eliminate persistent bacilli and minimize the risk of recurrence. A potent sterilizing drug that could shorten treatment to 2 months or less would be extremely beneficial. Drugs that facilitate acceptance by requiring less supervision are also needed. Obviously, a compound that could reduce total treatment length and the frequency of drug administration would provide the highest benefit.

The complicating factor in epidemic TB is the increasing incidence of multidrug-resistant mumps or MDR-TB. Up to 4% of all cases worldwide are considered MDR-TB - those resistant to the most effective 4-drug standard, isoniazid è rifampin. MDR-TB is lethal when untreated and cannot be adequately treated by standard therapy, so treatment may require up to 2 years of "second-line" drugs. These drugs are usually toxic, expensive and marginally effective. In the absence of effective therapy, infectious MDR-TB patients continue to spread the disease, producing new infections with MDR-TB strains. Therefore, there is a marked medical need for a new drug with a new mechanism of action that is likely to demonstrate counter-drug activity, in particular MDR strains.

The term "drug resistant" as used hereinbefore or hereinafter is a term well understood by one of ordinary skill in the art of microbiology. A drug resistant Mycobacterium is a Mycobacterium that is no longer sensitive to at least one previously effective drug and has developed the ability to withstand the anti-biotic attack of at least one previously effective drug. A drug resistant strain can supply this ability to support its progeny. Such resistance may be due to random genetic mutations in the bacterial cell that alter its sensitivity to a single drug or to different drugs.

MDR tuberculosis is a specific form of drug-resistant tuberculosis, due to a bacteria resistant to at least isoniazid erifampicin (with or without resistance to other drugs), which are present in the two most potent anti-TB drugs. Thus, whenever "drug resistant" is used, as above and hereinafter, it should be understood as multi-drug resistant.

Another factor in the control of epidemic TB is the la-try TB problem. Despite decades of tuberculosis control programs, around 2 billion people are infected with M. tuberculosis, albeit asymptomatically. About 10% of these individuals are at risk of developing active TB during their life cycle. The global TB epidemic is fueled by the infection of HIV patients with TB and grows with the participation of multidrug-resistant TB (MDR-TB) strains. Latent TBactivation is a high risk factor for disease development, accounting for 32% of deaths in HIV-infected individuals. To control epidemic TB, new drugs that can kill the dormant or dormant bacillus must be discovered. Inactive TB may become reactivated, causing disease due to several factors, such as suppression of host immunity through the use of immunosuppressive agents, such as antibodies against tumor necrosis factor α or interferon-γ. In HIV-positive patients, the only prophylactic treatment available for latent TB is two or three months of rifampin and pyrazinamide regimen. The effectiveness of the treatment regimen is still unclear and, moreover, the duration of treatments is a major limitation in resource-constrained environments.

As a result, there is a drastic need to identify new drugs that may act as chemoprophylactic agents in individuals with the latent TB bacillus.

Tubercle bacilli (causing tuberculosis) enter healthy individuals through inhalation; they are phagocytosed by the alveolar macrophages of the lungs. This leads to a potent immune response and formation of granulomas, which consist of macrophages infected by the T cell enveloped M. tuberculosis. After a period of 6-8 weeks, the host immune response causes the death of the infected cells by necrosis and the accumulation of caseous material with certain extracellular bacilli, enveloped by macrophages, epithelial cells and tissue lymphoid layers in the periphery. In the case of healthy individuals, most mycobacteria are killed in these environments, but a small proportion of disabled children are still surviving and are thought to exist in a non-duplicative hypomobolic state, being tolerant to death by anti-TB drugs, like isoniazid. These bacilli may remain in altered physiological environments, even for the life of individuals, without showing any clinical symptoms of the disease. However, in 10% of cases, these latent bacilli can be reactivated, causing the disease. Hypothyroidism about the development of these persistent bacteria is the pathophysiological environment that occurs in human lesions, namely reduced oxygen tension, nutrient limitation, and acidic pH. These factors have been postulated to make these bacteria phenotypically tolerant of the main antimicrobial drugs.

In addition to taking care of epidemic TB, there is the emerging problem of resistance to first-line antibiotic agents. Important examples include pe-nicillin-resistant Streptococcus pneumoniae, vancomycin-resistant Enterococci, methicillin-resistant Staphylococcus aureus, and multiresistant Salmonellae.

The consequences of resistance to antibiotic agents are severe. Infections caused by resistant microbes fail to respond to treatment, resulting in prolonged illness and increased risk of death. Treatment failures also provide long periods of disinfection, which increases the number of infected people moving in the community, thereby exposing the general population to the risk of contracting a resistant strain infection. Hospitals are a critical component of the antimicrobial resistance problem worldwide. Combination of highly sensitive patients and prolonged and intense use of antimicrobial drugs, in addition to cross-infection, has resulted in in-closures with highly resistant bacterial pathogens.

Self-medication with antimicrobial agents is another major contributor to resistance. Self-medicated antimicrobial agents may be unnecessary, are usually inadequately dosed, or may not contain adequate amounts of the active drug.

Patient acceptance of the recommended treatment is another major problem. Patients forget to take their medication, discontinue their treatment when they begin to feel better, or are unable to sustain a full course of treatment, thus creating an ideal environment for microbes to adapt rather than be killed.

Due to emerging resistance to multiple antibiotics, doctors are faced with infections for which there is no effective therapy. The morbidity, mortality, and financial costs of such infections impose a growing responsibility on public health systems worldwide.

Therefore, there is a great need for new compounds for treating bacterial infections, especially mycobacterial infections, including drug resistant and mycobacterial infections, as well as other bacterial infections, especially those caused by resistant bacterial strains.

WO 2004/011436, WO2005 / 070924, WO 2005/070430 and WO 2005/075428 describe certain substituted quinoline derivatives which have activity against My-cobacteria, in particular Mycobacterium tuberculosis. A particular compound of such substituted quinoline derivatives is described in Science (2005), 307, 223-227.

Other substituted quinolines are disclosed in U.S. Patent No. 5,965,572, for treatment of antibiotic resistant infections and WO 00/34265, to inhibit the growth of bacterial microorganisms.

The object of the present invention is to provide novel compounds, in particular substituted quinoline derivatives, having the property of inhibiting bacterial growth, especially of mycobacteria, thereby being useful in the treatment of mycobacterial diseases, particularly , those diseases caused by pathogenic mycobacteria, such as Mycobacterium tuberculosis (including latent drug-resistant M. tuberculosis strains), M. bovis, M. avium and M. ma-rinum. The compounds are also useful in treating other bacterial infections as described below.

The compounds according to the present invention are characterized by the presence of a tertiary nitrogen atom at the alpha position in the side chain fixed at position 3 of the quinoline core and thus have a different basic structure than the quinoline derivatives. described in the aforementioned patent document WO 2004/011436, which discloses an asymmetric carbon atom at that position. The compounds of the present invention therefore have the advantage that they are capable of forming fewer enantiomers than the compounds of WO 2004/011436,

Summary of the Invention

The present invention relates to novel substituted quinoline derivatives according to Formula (Ia) or Formula (Ib): <formula> formula see original document page 8 </formula>

pharmaceutically acceptable acid or base addition salts thereof, quaternary amines thereof, stereochemically isomeric forms thereof, tautomeric forms thereof, N-oxide dosage forms or prodrugs thereof, wherein:

- ρ is an integer equal to 0, 1, 2, 3 or 4;

q is an integer equal to 0, 1, 2 or 3;

- Z is a radical selected from the formulas:

<formula> formula see original document page 8 </formula>

OR

R1 is cyano, halo, alkyl, haloalkyl, hydroxy, alkyloxy, alkylthio, alkyloxyalkyl, alkylthioalkyl, arylalkyl, di (aryl) alkyl, aryl or Het;

R2 is hydrogen, alkyloxy, aryl, aryloxy, hydroxy, mercapto, alkyloxyalkyloxy, alkylthio, mono- or di (alkyl) amino, pyrrolidine or a radical of the formula wherein Y is CH2, O, S, NH or N-alkyl ;

R3 is alkyl, arylalkyl, aryl, mono- or di-alkylaminoalkyl, Het or Het-alkyl;

- R4 and R5 each independently is hydrogen; alkyl, alkyloxyalkyl; arylalkyl; Hetalkyl; mono- or dialkylaminoalkyl; Het; ouarila; or

- R4 and R5 together with the nitrogen atom to which they are attached form a radical selected from the group consisting of pyrrolidine, piperidino, piperazine, morpholine, 4-thiomorpholino, 2,3-dihydroisoindol-1-yl, thiazo-lidin-3 -ila, 1,2,3,6-tetrahydropyridyl, 1,4-diazacycloeptyl, 1-aza-4-oxacycloeptyl, 1,2,3,4-tetrahydroisoquinolin-2-yl, 2H-pyrrolyl, pyrrolinyl, pyrrolyl, imidazolidini -Ia, pyrazolidinyl, 2-imidazolinyl, 2-pyrazolinyl, imidazolyl, pyrazolyl, triazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl and triazinyl, optionally substituted by one or more substituents each independently selected from alkyl, haloalkyl, haloalkyl, hydroxy, alkyloxy, amino, mono- or dialkylamino, alkylthio, alkyloxyalkyl, alkylthioalkyl, aryl, pyridyl or pyrimidinyl;

R6 is aryl or Het;

R7 is hydrogen, halo, alkyl, aryl or Het;

- R8 is a straight chain or branched saturated hydrocarbon radical having from 1 to 6 carbon atoms;

R9 is hydrogen or alkyl;

R10 is oxo; and

-Xe-CH 2 -OR-CO-;

Alkyl is a straight chain or branched saturated hydrocarbon radical having from 1 to 6 carbon atoms; or is a cyclic saturated hydrocarbon radical having from 3 to 6 carbon atoms; or is a cyclic saturated hydrocarbon radical having from 3 to 6 carbon atoms attached to a straight or branched chain saturated hydrocarbon radical having from 1 to 6 carbon atoms; wherein each carbon atom may be optionally substituted by cyano, hydroxy, alkyloxy or oxo;

Aryl is a homocycle selected from phenyl, naphthyl, acenaphthyl or tetrahydronaphthyl, each optionally substituted by 1, 2 or 3 substituents, each substituent being independently selected from hydroxy, halo, cyano, nitro, amino, mono- or dialkylamino, alkyl, haloalkyl, alkyloxy, carboxyl, alkyloxycarbonyl, aminocarbonyl, morpholinyl or mono or dialkylaminocarbonyl;

Het is a monocyclic heterocycle selected from N-phenoxypiperidinyl, piperidinyl, pyrrolyl, pyrazolyl, imidazolyl, furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl; or a bicyclic heterocycle selected from quinolinyl, quinoxyalkyl, indolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzofuranyl, benzothienyl, 2,3-dihydrobenzo [1,4] dioxinyl orbenzo [1,3] dioxolyl; each monocyclic and bicyclic heterocycle being optionally substituted by 1, 2 or 3 substituents, each substituent independently being selected from halo, hydroxy, alkyl or alkyloxy;

Halo is a substituent selected from fluorine, chlorine, bromine or iodine; and

Haloalkyl is a saturated or branched chain hydrocarbon radical having from 1 to 6 carbon atoms or a cyclic saturated hydrocarbon radical having from 3 to 6 carbon atoms or a cyclic saturated hydrocarbon radical having from 3 to 6 carbon atoms. carbon attached to a straight chain or branched saturated hydrocarbon having from 1 to 6 carbon atoms; wherein one or more carbon atoms are replaced by one or more halogen atoms.

Unless otherwise indicated, the above compounds according to Formula (Ia) or Formula (Ib), the pharmaceutically acceptable acid addition or debase salts thereof, the quaternary amines thereof, the stereochemically isomeric forms thereof the tautomeric forms thereof, the N-oxide forms thereof or the prodrugs thereof will hereinafter be referred to as the compounds according to the invention.

The compounds according to Formulas (Ia) and (Ib) are inter-correlated wherein, for example, a compound according to Formula (Ib), with R10 equal to oxo, is the tautomeric equivalent of a compound. according to Formula (Ia), with R 2 equal to hydroxy (keto-tautomerism).

In the definition of Het, it is idealized to include all possible isomeric forms of heterocycles, for example, pyrrolyl comprises 1H-pyrrolyl and 2 / - / - pyrrolyl.

The aryl or Het group listed in the definitions of the substituents of the compounds of Formula (Ia) or (Ib) (see, for example, R3), as mentioned above or hereinafter, may be attached to the remainder of the Formula (Ia) molecule. or (Ib) through any carbon or ring heteroatom, if appropriate, unless otherwise specified. Thus, for example, when Het is imidazolyl, it may be 1-imidazolyl, 2-imidazolyl, 4-imidazolyl and the like.

Lines drawn from substituents within ring systems indicate that the bond may be attached to any suitable ring atoms.

Pharmaceutically acceptable acid addition salts are defined as comprising the therapeutically active and non-toxic acid addition salt forms that the compounds according to Formulas (Ia) or (Ib) are capable of forming. Said acid addition salts may be obtained by treating the base form of the compounds according to Formulas (Ia) or (Ib) with appropriate acids, for example inorganic acids such as hydroalic acids, in particular, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid; organic acids, for example, acetic acid, hydroxyacetic acid, propanoic acid, lactic acid, pyruvic acid, oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclamic acid, salicylic acid, p-aminosalicylic acid and pamoic acid.

Compounds according to Formulas (Ia) or (Ib) containing acidic protons may also be converted to their therapeutically active and non-toxic base salt forms by treatment with appropriate organic and inorganic bases. Suitable forms of base salts include, for example, ammonium salts, alkali metal and alkaline earth metal salts, in particular lithium, sodium, potassium, magnesium and calcium salts, salts with alkali metals. such as benzathine, N-methyl-D-glycamine, hibramine salts and salts with amino acids, for example arginine and lysine. Conversely, said acid addition or debase salt forms can be converted. in free forms by treatment with an appropriate base or acid.

The term addition salt as used in the structure of the present application also includes solvates which compounds according to Formulas (Ia) or (Ib), as well as salts thereof, are capable of forming. Such solvates are, for example, hydrates and alcoholates.

The term "quaternary amine" as used above defines the quaternary ammonium salts that the compounds of Formula (Ia) or (Ib) are capable of forming by reaction between a basic nitrogen of a compound of Formula (Ia) or ( Ib) with a quaternizing agent, such as, for example, an optionally substituted alkyl halide, arylalkyl halide, alkylcarbonyl halide, Ar-carbonyl halide, Het-alkyl halide or Het-carbonyl halide, for example , methyliodide or benzyliodide. Preferably, Het represents a selected monocyclic furanyl or thienyl heterocycle; or a bicyclic heterocycle selected from benzofuranyl or benzothienyl; each monocyclic and bicyclic heterocycle may optionally be substituted by 1, 2 or 3 substituents, each substituent independently selected from the group of halo, alkyl and Ar. Preferably, the quaternizing agent is an alkyl halide. Other reagents with satisfactory leaving groups may also be used, such as alkyl trifluoromethanesulfonates, alkyl methanesulfonates and alkyl p-toluenesulfonates. A quaternary amine has a positively charged nitrogen. Pharmaceutically acceptable backload ions include chlorine, bromine, iodine, trifluoroacetate, acetate, triflate, sulfate, sulfonate. Preferably the backload ion is iodine. The counter-charge ion of choice can be introduced using ion exchange resins.

The term "stereochemically isomeric forms" as used above and hereinafter defines all possible stereoisomeric forms that the compounds of Formulas (Ia) and (Ib) and their physiologically functional N-oxides, addition salts or derivatives may possess. Unless otherwise stated or indicated, the chemical designation of the compounds indicates the mixture of all possible stereo-chemically isomeric forms, said mixtures containing all diastereomers and enantiomers of basic molecular structure. In particular, stereogenic centers may have the R or S configurations; substituents on (partially) saturated cyclic bivalent radicals may have an eis- or trans- configuration. Compounds comprising double bonds may exhibit E (entgegeri) or Z (zuzam-meri) stereochemistry

In said double bond. The terms useful, trans, R, S, E and Z are well known to one skilled in the art. Stereochemically isomeric forms of the compounds of Formulas (Ia) and (Ib) are obviously intended to be encompassed within the scope of the present invention.

According to CAS naming conventions, when two stereogenic centers of absolutely known configuration are present in a molecule, an R or S descriptor (based on Cahn-Ingold-Prelog sequence sequence) is assigned to the lowest numbered chiral center. reference Center. The setting of the second stereogenic center is indicated using relative descriptors [R *, R *] or [R *, S *], where R * is always specified as the reference center and [R *, R *] indicates the centers. with the same chirality and [R *, S *] indicates different chirality centers. For example, if the lowest numbered chiral center in the molecule has a Seo second center setting is R, the stereo descriptor would be specified as S- [R *, S *]. If "a" and "β" are used: the position of the highest priority substituent on the asymmetric carbon atom in the ring system having the lowest number of rings is always arbitrarily the position "a" of the midplane determined by the system. Ring The position of the highest priority substituent on the other asymmetric carbon atom in the ring system relative to the position of the highest priority substituent on the reference atom is called "a", if it is the same side of the midplane determined by the carbon system. ring or "β" if the same is on the other side of the midplane determined by the ring system.

When a specific stereoisomeric form is indicated, it means that said form is substantially free, that is, it is associated with less than 50%, preferably less than 20%, more preferably less than 10%, even more preferably less than 50%. 5%, even more preferably less than 2% and even more preferably less than 1% of the other isomer (s). Thus, when a compound of Formula (I) is, for example, specified as (aS, pR), it means that the compound is substantially free of the isomer (aR.pS).

The compounds of Formulas (Ia) and (Ib) may be synthesized as racemic mixtures of enantiomers which may be separated from each other according to well known decomposition procedures. Racemic compounds of Formulas (Ia) and (Ib) may be converted to the corresponding diastereomeric salt forms by reaction with a suitable chiral acid. Said diastereomeric salt forms are sequentially separated, for example by selective or fractional crystallization and the enantiomers are released from them by alkali. An alternative way of separating the enantiomeric forms from the compounds of Formula (Ia) and ( Ib) involves the liquid chromatography procedure using a chiral stationary phase. Said stereochemically pure isomeric forms may also be derived from the corresponding stereochemically pure isomeric forms of the appropriate starting materials, provided that the reaction occurs stereospecifically. Preferably, if a specific stereoisomer is desired, said compound will be synthesized by stereospecific separation methods. Such methods will advantageously use enantiomerically pure starting materials.

Tautomeric forms of the compounds of Formula (Ia) or (Ib) are ideally comprised of those compounds of Formula (Ia) or (Ib) wherein, for example, an enolic group is converted to a keto group (ketoenolic tau-tomerism) .

The N-oxide forms of the present compounds are ideally comprised of the compounds of Formulas (Ia) or (Ib), wherein one or more tertiary nitrogen atoms are oxidized to the so-called N-oxide.

The compounds of Formulas (Ia) and (Ib) may be converted to the corresponding N-oxide forms according to procedures known in the art for converting a trivalent nitrogen into its N-oxide form. Said N-oxidation reaction can generally be accomplished by reacting the starting material of Formula (I) with an appropriate organic or inorganic peroxide. Suitable inorganic peroxides include, for example, hydrogen peroxide, alkali metal or alkaline earth metal peroxides, for example sodium peroxide, potassium peroxide, suitable organic peroxides may comprise paroxy acids, such as, for example. benzene carboperoxic acid or halogen substituted benzene carboperoxic acid, for example 3-chlorobenzene carboperoxic acid, peroxoalkanoic acids, for example peroxyacetic acid; alkyl hydroperoxides, for example t-butyl hydroperoxide. Suitable solvents are, for example, water, lower alcohols, for example ethanol and the like; hydrocarbons, for example toluene; ketones, for example 2-butanone; halogenated hydrocarbons, for example dichloromethane and mixtures of such solvents.

The invention also encompasses compounds derived (commonly referred to as "prodrugs") from pharmacologically reactive compounds according to the invention which are broken down in vivo to produce compounds according to the invention. Prodrugs are usually (but not always) of lower pharmacological activity in the target receptor than the compounds to which they are broken down.

Prodrugs are particularly useful when the desired compound has chemical or physical properties that make its administration difficult or inefficient. For example, the desired compound may be poorly soluble feathers, may be poorly transported through mucosal epithelium or may have an undesirable short plasma half-life. Further details on prodrugs can be found in the publication of Stella V. J. et al, "Prodrugs", Drug Delivery Systems, 1985, pages 112-176, and Drugs, 1985, 29, pages 455-473,

The prodrug forms of the pharmacologically reactive compounds according to the invention will generally be the compounds according to Formulas (Ia) or (Ib), the pharmaceutically acceptable acid or base addition salts thereof, the stereochemically isomeric forms thereof. -they are the tautomeric forms thereof and the N-oxide forms thereof having an acidic group which is esterified or amidated. Included in such esterified acid groups are the groups of formula -COORx, where Rx is C1-6 alkyl, phenyl, benzyl or one of the following groups:

<formula> formula see original document page 16 </formula>

Amidated groups include the groups of formula -CONRyRz, where Ry is H, C1-6 alkyl, phenyl or benzyl and Rz is -OH, H, C1-6 alkyl, phenyl or benzyl.

The compounds according to the invention having an amino group may be derivatized with a ketone or an aldehyde, such as a formaldehyde, to form a Mannich base. This base will hydrolyze as the first kinetic order in aqueous solution.

Preferably alkyl is a straight or branched saturated hydrocarbon radical having from 1 to 6 carbon atoms selected from methyl, ethyl, propyl or butyl; or a cyclic saturated hydrocarbon radical having from 3 to 6 carbon atoms selected from cyclopropyl or cyclohexyl, optionally substituted by cyano. Or alkyl is C1-6 alkyl. C 1-6 alkyl-1a is a straight or branched chain saturated hydrocarbon radical having from 1 to 6 carbon atoms, such as, for example, methyl, ethyl, propyl, 2-methylethyl, pentyl, hexyl and the like. A preferred subgroup of C1-6 alkyl is C1-4 alkyl which represents a branched or branched saturated hydrocarbon radical having from 1 to 4 carbon atoms, such as, for example, methyl, ethyl, propyl, 2- methyl ethyl and the like. Preferably, aryl is naphthyl or phenyl, more preferably phenyl, each optionally substituted by one or two selected halo substituents, for example chlorine; alkyl, for example methyl; or alkoxy, for example methyloxy.

Preferably, Het is furanyl, pyridyl, pyrimidyl, quinolinyl or benzofuranyl.

Preferably halo is bromine, fluorine or chlorine.

Preferably haloalkyl is trifluoromethyl;

The compounds of Formula (Ia) are generally preferred.

Preferably, the present invention relates to a compound of Formulas (Ia) or (Ib) or any subgroup thereof, as mentioned above as a preferred embodiment, wherein R 1 is halo, aryl, alkyl or aryloxy; or wherein R1 is halo, cyano, alkyl or Het. More preferably, R1 is halo. Even more preferably, R 1 is bromo.

Preferably, the present invention relates to a compound of Formulas (Ia) or (Ib) or any subgroup thereof, as mentioned above as a preferred embodiment, where ρ is equal to O or 1,

For the compounds of Formula (Ia), preferably, the present invention relates to a compound of Formula (Ia) or any subgroup thereof, as mentioned above as a preferred embodiment, wherein R2 is alkyloxy, aryl, aryloxy or Het in particular. alkyloxy, aryl, asryloxy or pyrrolidine. More preferably, R2 is alkyloxy or aryl. More preferably, R 2 is methyloxy or phenyl.

For the compounds of Formula (Ib), preferably, the present invention relates to a compound of Formula (Ib) or any subgroup thereof, as mentioned above as a preferred embodiment, wherein R 9 is alkyl and R 10 is oxo.

Preferably, the present invention relates to a compound of Formulas (Ia) or (Ib) or any subgroup thereof, as mentioned above as a preferred embodiment, wherein R3 is alkyl, arylalkyl, aryl, mono- or dialkylaminoalkyl. or Het-alkyl, for example furanyl-, pyridyl- or quinolinyl-alkyl, more preferably Het-methyl, more preferably furanyl-, pyridyl- or quinolinyl-methyl.

Preferably, the present invention relates to a compound of Formulas (Ia) or (Ib) or any subgroup thereof, as mentioned above as a preferred embodiment, where q is 1 or 2, More preferably, q is 1 ,

Preferably, the present invention relates to a compound of Formulas (Ia) or (Ib) or any subgroup thereof, as mentioned above as a preferred embodiment, wherein Het in the definition of substituent R4 or R5 is pyridinyl or benzofuranyl.

For the compounds of Formulas (Ia) or (Ib), wherein Z is a radical of formula (a), preferably the present invention relates to a compound of Formulas (Ia) or (Ib) or any subgroup thereof. as mentioned above as a preferred embodiment, wherein R 4 and R 5 each independently represent hydrogen or alkyl, more preferably hydrogen, methyl or ethyl, most preferably methyl.

Preferably, the present invention relates to a compound of Formulas (Ia) or (Ib) or any subgroup thereof, as mentioned above as a preferred embodiment, wherein R 4 and R 5 together with the nitrogen atom to which they are attached form. a radical selected from pyrrolidine, piperidino, piperazine, morpholine, 4-thiomorpholino, 2,3-dihydroisoindol-1-yl, thiazolidin-3-yl, 1,2,3,6-tetrahydropyridyl, 1-aza-4-oxacycloeptyl, 1 4-diazacycloeptyl or 1,2,3,4-tetrahydroisoquinolin-2-yl optionally substituted by one or two substituents, more preferably one substituent selected from alkyl, arylalkyl, aryl, pyridyl or pyrimidinyl.

For the compounds of Formulas (Ia) or (Ib), wherein Z is a radical of formula (b), preferably the present invention relates to a compound of Formulas (Ia) or (Ib) or any subgroup thereof. as mentioned above as a preferred embodiment, wherein R 8 is a straight or branched chain saturated hydrocarbon radical having from 1 to 4 carbon atoms, preferably methyl or ethyl.

Preferably, the present invention relates to a compound of Formulas (Ia) or (Ib) or any subgroup thereof, as mentioned above as a preferred embodiment, wherein R 6 is phenyl or Het, for example benzofuranyl or pyridinyl, each optionally being substituted by one or two substituents independently selected from halo or alkyl.

Preferably, the present invention relates to a compound of Formulas (Ia) or (Ib) or any subgroup thereof, as mentioned above as a preferred embodiment, wherein R 7 is hydrogen or halo, for example chlorine.

Preferably, the present invention relates to a compound of Formulas (Ia) or (Ib) or any subgroup thereof, as mentioned above as a preferred embodiment, wherein R 9 is alkyl, more preferably C 1-6 alkyl, for example. , methyl.

Preferably, the present invention relates to a compound of Formulas (Ia) or (Ib) or any subgroup thereof, as mentioned above as a preferred embodiment, wherein Z is a radical of formula (a).

Preferably, the present invention relates to a compound of Formulas (Ia) or (Ib) or any subgroup thereof, as mentioned above as a preferred embodiment, wherein Z is a radical of formula (b).

A preferred group of compounds are those compounds according to Formula (Ia), the pharmaceutically acceptable acid or base addition salts thereof, the quaternary amines thereof, the stereochemically isomeric forms thereof, the tautomeric forms thereof. same, the N-oxide forms thereof or the prodrugs thereof, where ρ is 0 or 1; R2 is alkyloxy, aryl, aryloxy or Het; R3 is alkyl, arylalkyl, aryl, mono- or di-alkylaminoalkyl or Het-alkyl; q equals 1 or 2; R4 and R5 each independently is hydrogen; alkyl; alkyloxyalkyl; arylalkyl; Hetalkyl; mono- or di-alkylaminoalkyl; Het; ouarila; or R4 and R5 together with the nitrogen atom to which they are attached form a radical selected from pyrrolidine, piperidino, piperazine, morpholine, 4-thiomorpholino, 2,3-dihydroisoindol-1-yl, thiazolidin-3-yl, 1,2,3,6-tetrahydropyridyl, 1-aza-4-oxacycloeptyl, 1,4-diazacycloeptyl, or 1,2,3,4-tetrahydroisoquinolin-2-yl, optionally substituted by one or two substituents, more preferably a substituent selected from alkyl, arylalkyl, aryl, pyridyl or pyrimidinyl; R6 is phenyl or Het; R7 is hydrogen or halo; R 8 is a straight chain or branched saturated hydrocarbon radical having from 1 to 4 carbon atoms; R9 is alkyl; R10 is oxo.

An especially preferred group of compounds are those compounds according to Formula (Ia), the pharmaceutically acceptable acid or base addition salts thereof, the quaternary amines thereof, the stereochemically isomeric forms thereof, the tautomeric forms thereof, N-oxide thereof or the prodrugs thereof, where ρ is 0 or 1; R1 is halo, especially bromo or alkyl, especially methyl, preferably at position 6; R2 is alkyloxy, especially methyloxy or aryl, especially phenyl; R3 is aryl, especially phenyl, arylalkyl, especially benzyl or Het-alkyl, especially quinoline-5-ylmethyl; q is 1; R 4 and R 5 each independently are alkyl, especially methyl, ethyl or isopropyl, or R 4 and R 5 together with the nitrogen atom to which they are attached form a 4-thiomorpholine, piperidino or piperazine radical, substituted by alkyl, especially methyl, at position 4, or by arylalkyl, especially benzyl; R 6 is aryl, especially phenyl, optionally substituted by a halogen, especially fluorine, preferably at position 2 or R 6 is benzofuranyl; R7 is hydrogen; and R8 is a straight chain or branched saturated hydrocarbon radical having from 1 to 4 carbon atoms, especially ethyl.

Another especially preferred group of compounds which exhibit activity against mycobacteria are those compounds according to Formula (Ia), the pharmaceutically acceptable acid or base addition salts thereof, the quaternary amines thereof, the forms thereof. stereochemically isomeric thereof, the tautomeric forms thereof, the N-oxide forms thereof or the prodrugs thereof, where ρ is 1; Z is a radical of formula (a); R1 is bromo or methyl, preferably at position 6; R 2 is methyloxy or phenyl; R3 is phenyl optionally substituted by methyloxy or benzyl; q is 1; R4 and R5, each independently, are methyl, ethyl or isopropyl, or R4 and R5 together with the denitrogen atom to which they are attached form a methyl-substituted 4-thiomorpholine radical, a piperidino radical, in the position 4, or a benzyl substituted piperazine radical at position 4; R6 is phenyl or benzofuranyl and R7 is hydrogen.

Another especially preferred group of compounds which exhibit activity against bacteria other than mycobacteria are those composed according to Formula (Ia), the pharmaceutically acceptable acid or base addition salts thereof, the quaternary amines thereof, the stereochemically isomeric forms thereof. same, their tautomeric forms, their N-oxide forms or their prodrugs, where ρ is 0 or 1; R1 is bromo or methyl, preferably at position 6; R 2 is methyloxy or phenyl; R3 is phenyl, benzyl or quinolin-5-ylmethyl; q is 1; R 4 and R 5 each independently are methyl, or R 4 and R 5 together with the nitrogen atom to which they are attached form a methyl-substituted piperazine radical at position 4; R6 is phenyl, optionally substituted by fluorine in position 2; R7 is hydrogen; and R8 is ethyl.

More preferably, for activity against batteries other than mycobacteria, the compound is selected from:

2- {benzyl - [(6-methyl-2-phenyl-quinolin-3-yl) -phenyl-methyl] -amino} -N- (4-methyl-piperazin-1-yl) -acetamide;

N - [(6-bromo-2-methoxy-quinolin-3-yl) -phenyl-methyl] -N ', N'-dimethyl-N-phenyl-ethane-1,2-diamine;

N-benzyl-N - [(6-bromo-2-phenyl-quinolin-3-yl) -phenyl-methyl] -N ', N-dimethyl-ethane-1,2-diamine;

2- {benzyl - [(6-methyl-2-phenyl-quinolin-3-yl) -phenyl-methyl] -amino} -1- (4-methyl-piperazin-1-yl) -ethanone;

2 - {[(6-bromo-2-methoxy-quinolin-3-yl) -phenyl-methyl] -quinolin-5-ylmethyl-aminmethyl-piperazin-1-yl) -ethanone;

2- {benzyl - [(6-bromo-2-methoxy-quinolin-3-yl) -phenyl-methyl] -amino} -1- (4-methyl-piperazin-1-yl) -ethanone;

N-benzyl-N - [(6-bromo-2-methoxy-quinolin-3-yl) - (2-fluoro-phenyl) -methyl] -N11 N'-dimethyl-ethane-1,2-diamine;

{Benzyl - [(6-bromo-2-methoxy-quinolin-3-yl) -phenyl-methyl] -amino-acetic acid ethyl ester; and

2- {benzyl - [(6-methyl-2-phenyl-quinolin-3-yl) -phenyl-methyl] -amino} -1-piperidin-1-yl-ethanone;

and the pharmaceutically acceptable acid or base addition salts thereof, the quaternary amines thereof, the stereochemically isomeric forms thereof, the tautomeric forms thereof, the N-oxide forms thereof or the prodrugs thereof.

More preferably, for activity against mycobacteria, the compound is selected from:

2- {benzyl - [(6-methyl-2-phenyl-quinolin-3-yl) -phenyl-methyl] -amino} -1- (4-benzyl-piperazin-1-yl) -ethanone;

N - [(6-bromo-2-methoxy-quinolin-3-yl) -phenyl-methyl] -N- (2-methoxy-phenyl) -N ', N-dimethyl-ethane-1,2-diamine;

2- {benzyl - [(6-methyl-2-phenyl-quinolin-3-yl) -phenyl-methyl] -amino} -N, N-dimethyl acetamide;

N-benzyl-N - [(6-bromo-2-phenyl-quinolin-3-yl) -phenyl-methyl] -N ', N'-dimethyl-ethane-1,2-diamine;

2- {benzyl - [(6-methyl-2-phenyl-quinolin-3-yl) -phenyl-methyl] -amino} -1- (4-methyl-piperidin-1-yl) -ethanone;

2- {benzyl - [(6-methyl-2-phenyl-quinolin-3-yl) -phenyl-methyl] -amino} -N, N-diethyl-acetamide;

2- {benzyl - [(6-bromo-2-phenyl-quinolin-3-yl) -phenyl-methyl] -amino} -N, N-dimethyl-acetamide;

2 - {[benzofuran-2-yl- (2-phenyl-quinolin-3-yl) -methyl] -benzyl-amino} -N-isopropyl-N-methyl-acetamide;

2- {benzyl - [(6-methyl-2-phenyl-quinolin-3-yl) -phenyl-methanone; and

2- {benzyl - [(6-methyl-2-phenyl-quinolin-3-yl) -phenyl-methyl-acetamide;

and the pharmaceutically acceptable acid or base addition salts thereof, the quaternary amines thereof, the stereochemically isomeric forms thereof, the tautomeric forms thereof, the N-oxide forms thereof or the prodrugs thereof.

Pharmacology

The compounds according to the invention have been surprisingly shown to be suitable for the treatment of bacterial diseases, including especially mycobacterial diseases, particularly those diseases caused by pathogenic mycobacteria, such as Mycobacterium tuberculosis (including latent disease). drug-resistant M. tuberculosis strains), M. bovis, M. avium and M. marinum. The present invention also relates to compounds of Formulas (Ia) or (Ib) as defined above, to the acceptable acid or base pharmaceutically acceptable addition salts thereof, to the quaternary amines thereof, to the stereochemically isomeric forms thereof; their tautomeric forms, their N-oxide forms or their prodrugs for use as a medicament.

Further, the present invention relates to the use of a compound of Formulas (Ia) or (Ib), pharmaceutically acceptable acid addition or base salts thereof, quaternary amines thereof, stereochemically isomers thereof, tautomeric forms thereof, N-oxide forms thereof or prodrugs thereof, as well as any of the pharmaceutical compositions thereof as described above or hereinafter in the manufacture of a medicament for treating a bacterial disease, including a mycobacterial disease.

Accordingly, in another aspect, the invention provides a method of treating a patient suffering from or at risk of bacterial disease, including a mycobacterial disease, which method comprises administering to the patient a therapeutically effective amount of a pharmaceutical compound or composition according to the invention.

In addition to their activity against mycobacteria, the compounds according to the invention may also be active against other bacteria.

In general, bacterial pathogens can be classified as gram-positive pathogens or gram-negative pathogens. Antibiotic compounds with activity against gram-positive and gram-negative pathogens are generally considered to have a broad spectrum of activity. The compounds of the present invention are considered to be active against gram-positive and / or gram-negative bacterial pathogens. In particular, the present compounds are active against at least one gram-positive bacterium, preferably against several gram-positive bacteria, more preferably, one or more gram-positive bacteria and / or one or more gram-negative bacteria.

The present compounds exhibit bactericidal or bacteriostatic activity.

Examples of egram-negative gram-positive aerobic and anaerobic bacteria include, staphylococci, e.g., S. aureus, entente-rococo, e.g., E.faecalis, streptococci, e.g., S. pneumoniae, S. mutans, S. pyogens, bacilli, e.g., Bacillus subtilis-, alisteria, e.g., Listeria monocytogenes; hemophiles, for example H.influenza; moraxela, for example M. catarrhalis; pseudomonas, for example, Pseudomonas aeruginosa; and escherichia, for example, E. coli.

Gram-positive pathogens, for example staphylococci, enterococci and streptococci are particularly important because of the development of resistant strains that are difficult to treat and difficult to eradicate, for example, from a hospital setting once established. Examples of such strains include methicillin-resistant Staphylococcus aureus (MRSA), methicillin-resistant coagulase negative staphylococci (MRCNS) 1-penicillin-resistant S-treptococcus pneumoniae and Enterococcus faecium multidrug-resistant.

The compounds of the present invention also show activity against resistant bacterial strains.

The compounds of the present invention are especially active against Staphylococcus aureus, including resistant Staphyloeoeeus aureus, such as, for example, methicillin resistant Staphyloeoeeus aureus (MR-SA) and Streptoeoeeus pneumoniae.

In particular, the compounds of the present invention are active on those bacteria whose viability depends on the proper functioning of F1FO ATP synthase. Without wishing to be bound by any theoretical concept, it is thought that the activity of the present compounds resides in inhibiting F1FO ATP synthase, in particular in inhibiting the F1FO ATP synthase complex, more particularly in inhibiting the "c" subunit. "of the F1FO ATP synthase FO complex, leading to bacterial death by depleting the bacterial cellular ATP levels.

Bacterial infections that can be treated by the present compounds include, for example, central nervous system infections, external ear infections, middle ear infections, such as the acute otitis membrane, sinus infections. eye infections, oral cavity infections such as teeth, dagengiva and mucosal infections, upper respiratory tract infections, lower respiratory tract infections, genitourinary infections, gastrointestinal infections, gynecological infections, septicemia, bone and joint infections, skin infections and skin structure, bacterial endocarditis, burns, surgical antibacterial prophylaxis, and antibacterial prophylaxis in immunosuppressive patients, such as cancer chemotherapy or organ transplant patients.

As noted above or hereinafter, that the compounds may be used to treat a bacterial infection, it should be understood that the compounds may treat an infection with one or more bacterial strains. As mentioned above or hereinafter, the infection bacterial infection is different from a Mycobacterial infection, it should be understood that a bacterial infection is different from an infection with one or more Mycobacteria.

The invention also relates to a composition comprising a pharmaceutically acceptable carrier and, as active ingredient, a therapeutically effective amount of a compound according to the invention. The compounds according to the invention may be formulated into various pharmaceutical forms for administration purposes. As suitable compositions, all compositions commonly employed for systemic drug administration may be cited. To prepare the pharmaceutical compositions of the present invention, a particular effective compounding amount, optionally in the form of an addition salt as an active ingredient, is combined in intimate admixture with a pharmaceutically acceptable carrier, the carrier of which may take a wide variety of formulas. but, depending on the desired preparation form for administration. These pharmaceutical compositions are desirable in suitable unitary form, in particular for oral administration or parenteral injection. For example, in preparing the compositions in oral dosage form, any usual pharmaceutical medium may be used, such as, for example, water, glycols, oils, alcohols and the like in the case of liquid oral preparations, such as suspensions. syrups, elixirs, emulsions and solutions, or solid carriers such as starches, sugars, kaolin, diluents, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules and tablets. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit forms, in which case solid pharmaceutical carriers are obviously employed. For parenteral compositions, the carrier will usually comprise sterile water, at least for the most part, although other ingredients, for example to aid solubility, may be included. Injectable solutions, for example, may be prepared with the carrier comprising a saline solution, glucose solution or a mixture of saline and glucose solution. Injectable suspensions may also be prepared, in which case appropriate liquid vehicles, suspending agents and the like may be employed. Also included are solid form preparations, which are designed to be converted, shortly before use, to formaliquid preparations.

Depending on the mode of administration, the pharmaceutical composition will preferably comprise from 0.05 to 99% by weight, more preferably from 0.1 to 70% by weight of active ingredient and from 1 to 99.95% by weight. more preferably from 30 to 99.9% by weight of a pharmaceutically acceptable carrier, all percentages being based on the total weight of the composition.

The pharmaceutical composition may further contain a number of other ingredients known in the art, for example a lubricant, a sterilizing agent, a buffering agent, an emulsifying agent, a viscosity regulating agent, a surfactant, a preservative, a flavoring or coloring agent.

It is spatially advantageous to formulate the above-mentioned pharmaceutical compositions in unit dosage form for ease of administration and uniformity of dosage. The term unit dosage form as used herein refers to physically distinct units, suitable as unitary dosages, each unit containing a predetermined amount of active ingredient calculated to produce the desired therapeutic effect, in association with the required carrier. Examples of such unit dosage forms are tablets (including labeled or coated tablets), capsules, pills, powder bags, puffs, suppositories, injectable solutions or suspensions and the like and multiple derivatives thereof. The daily dosage of the compound according to the invention will, of course, vary according to the compound employed, the method of administration, the desired treatment and the mycobacterial disease indicated. However, in general, satisfactory results will be obtained when the compound according to the invention is administered at a daily dose of not more than 1 gram, for example, in the range of 10 to 50 mg / kg body weight.

Because the compounds of Formulas (Ia) or (Ib) are seremic against bacterial infections, the present compounds may be combined with other antibacterial agents in order to effectively counteract bacterial infections.

Therefore, the present invention relates to a combination of (a) a compound according to the invention and (b) one or more other antibacterial agents.

The present invention also relates to a combination of (a) a compound according to the invention and (b) one or more other antibacterial agents for use as a medicament.

The present invention also relates to the use of a combination or pharmaceutical composition as defined above for treating a bacterial infection.

A pharmaceutical composition comprising a pharmaceutically acceptable carrier and, as active ingredient, a therapeutically effective amount of (a) a compound according to the invention and (b) one or more other antibacterial agents, is also comprised by the present invention. invention.

The weight ratio of (a) the compound according to the invention and (b) the other antibacterial agent (s) when supplied as a combination may be determined by one of ordinary skill in the art. in technique. Said proportion and the exact dosage and frequency of administration depend upon the particular compound according to the invention and the other antibacterial agent (s) used, the particular condition being treated. the severity of the condition being treated, the age, dope, gender, regimen, time of administration and physical fitness of the particular patient, the mode of administration, as well as any other medication the individual may be taking, such as It is well known by those skilled in the art. Furthermore, it is apparent that the effective daily amount may be decreased or increased depending upon the response of the subject and / or depending on the judgment of the physician prescribing the compounds of the present invention.

The compounds according to the invention and one or more other antibacterial agents may be combined into a single preparation or may be formulated into separate preparations so that they may be administered simultaneously, separately or sequentially. Thus, the present invention also relates to a product containing (a) a compound according to the invention, and (b) one or more other antibacterial agents, in the form of a combined preparation for simultaneous, separate or sequential use. in the treatment of a bacterial infection.

Other antibacterial agents that may be combined with the compounds of Formulas (Ia) or (Ib) are antibacterial agents known in the art. Other antibacterial agents include β-lactam group antibiotics, such as natural penicillins, semisynthetic penicillins, natural cephalosporins, semisynthetic cephalosporins, cephalamines, 1-oxacephem, clavulanic acids, penem, carbapenem, nocardicins, monobactams; tetracyclines, anhydrotetracyclines, anthracyclines; aminoglycosides; nucleosides, such as N-nucleosides, C-nucleosides, carbocyclic nucleosides, blasticidine S; macrolides such as 12-membered ring macrolides, 14-membered ring macrolides, 16-membered ring macrolides, ansamycins; peptides, such as bleomycins, gra-mycidines, polymyxins, bacitracins, large ring peptide antibiotics containing lactone bonds, actinomycins, amphomycin, capreomycin, dis-tamycin, enduracidins, mycamycin, neocarzinostatin, stendomycin, vio-mycin, virginiamycin; cycloheximide; cycloserine; variotin, sarcomycin A, novobiocin, griseofulvin, chloramphenicol, mitomycin; fumagillin; monuments; pyrrolnitrin; phosphomycin; flusidic acid; D- (p-hydroxyphenyl) glycine; D-phenylglycine; enedunas.

Specific antibiotics which may be combined with the present compounds of Formulas (Ia) or (Ib) are, for example, benzylpenicillin (potassium, procaine, benzathine), phenoxymethylpenicillin (potassium), phenethylinapotassium, propicillin, carbenicillin (disodium, phenylene). sodium, indanyl sodium), sulbenicillin, disodium ticarcillin, sodium methicillin, sodium oxacillin, sodium cloxacin, dicloxacillin, flucloxacillin, ampicillin, mezlocillin, piperacillin, chloraccillin, hydrochloric acid, cyclicamine , cephalexin, ceflacor, cefaloglycine, cefadroxil, cefradine, cefroxadine, sodium cefapyrin, cephalothin sodium, cefaletrine sodium, cefaloridine, cefatrizine, cefophazodone, cephazodax, cephazodax, cefatrin soda cefmenoxime hydrochloride, cefuroxime, sodium ceftriaxone, sodium ceftazidime, cefox itin, cefmetazole, cefotetan, Yata-moxef, clavulanic acid, imipenem, aztreonam, tetracycline, decortetracycline hydrochloride, dimethylchortetracycline, oxytetracycline, metacycline, dioxocycline, rolitetracycline, hydrocyclic dibasicaminate hydrochloride, cyclocycline hydrochloride tobramycin, gen-tamycin sulfate, dibecacin, amikacin, micronomicin, ribostamycin, deneomycin sulfate, paromomycin sulfate, streptomycin sulfate, dihydrostrepomycin, destomycin A, hygromycin B, apramycin, sisomycin, denetylmycin sulfate hydrochloride astromycin, validamycin, casugamycin, polyoxin, blastieidine S, erythromycin, erythromycin stolate, oleandomycin phosphate, tracetyloleandomycin, quitasamycin, josami-kin, spiramycin, tylosin, ivermectin, midecamycin, sulecomycin, sulfate S, polymyxin B, bacitracin, decolistin sulfate, colistinmethanesulfon sodium act, enramycin, mycamicin, virginia-mycine, capreomycin sulfate, viomycin, enviomycin, vancomycin, actinomycin D, neocarzinostatin, bestatin, pepstatin, monensin, lasalocid, salinomycin, amphotericin B, nystatin, natamycin, tricaminin, , clindamycin, clindamycin palmitate hydrochloride, flavophospho-lipol, cycloserine, pecilocin, griseofulvin, chloramphenicol palmitate, mito-mycine C, pyrrolnitrin, phosphomycin, flusidic acid, biczamycin, thiamulin, sicanine.

Other mycobacterial agents which may be combined with the compounds of Formulas (Ia) or (Ib) are, for example, rifampicin (= rifampin); isoniazid; pyrazinamide; amikacin; etionamide; moxifloxacin ethambutol; streptomycin; p-aminosalicylic acid; cycloserine; capreomycin; kanamycin; thioacetazone; PA-824; quinolones / fluoroquinolones, such as, for example, ofloxacin, ciprofloxacin, sparfloxacin; macrolides, such as, for example, clarithromycin, clofazimine, amoxicillin with clavulanic acid; rifamycin; rifabutin; rifapentin.

General Preparation

The compounds according to the invention can generally be prepared by a succession of steps, each known to one skilled in the art.

Compounds of Formula (Ia) wherein Z is a radical of formula (a) wherein X is -CH 2 -, represented by Formula (Ia1) below, may be prepared by reacting a compound of Formula (II) with one with of Formula (III) according to Reaction Scheme 1 below:

Scheme 1

<formula> formula see original document page 31 </formula>

(wherein Y is a leaving group such as bromo, chloro, hydroxyl, p-toluenesulfonyloxy or methanesulfonyloxy). When Y is bromine, the reaction is usually carried out in the presence of a base such as potassium carbonate, sodium carbonate, Et 3 N and in a suitable solvent such as acetonitrile, dimethylformamide, N-methylpyrrolidone or diglyme. When Y is hydroxy, the reaction is usually carried out in the presence of P (Ph3) and diisopropylazodi carboxylate (DIAD) or diethylazodicarboxylate (DEAD) in a suitable solvent such as tetrahydrofuran.

Compounds of Formula (Ia) wherein Z is a radical of formula (b), represented by Formula (Ia2) below, may be prepared by reacting a compound of Formula (II) with a compound of Formula (IV). , according to Reaction Scheme 2, below: Scheme 2

<formula> formula see original document page 32 </formula>

The reaction may be carried out under conditions analogous to those described for Reaction Scheme 1, above.

The compounds of Formula (Ia2) may be converted to intermediate compounds of Formula (V) which may subsequently be reacted with a compound of Formula (VI) and converted to compounds of Formula (Ia), wherein Z is a compound. radical of Formula (a), wherein X is -CO-, represented by Formula (Ia3) below, as described in Reaction Scheme 3, below.

Scheme 3

<formula> formula see original document page 32 </formula>

In stage (a), the compound of Formula (Ia2) may be hydrolyzed, for example, by treatment with aqueous lithium hydroxide in an organic solvent, such as tetrahydrofuran. In stage (b) the intermediate compound of Formula (V) is reacted with an amine compound of Formula (VI), for example, in the presence of N-ethyl-N '- (3-dimethylaminopropyl) carbodiimide ( EDCI) and 1-hydroxybenzotriazole (HOBT) in the presence of a base such as triethylamine and in a suitable solvent such as dichloromethane and / or tetrahydrofuran.

The intermediate compound of Formula (II) wherein R 6 is aryl and Y bromine represented by Formula (IIaI) below may be prepared by bromination of a compound of Formula (VII) according to Reaction Scheme 4a below:

Scheme 4a

<formula> formula see original document page 33 </formula>

Bromination of the compound of Formula (VII) may be effected, for example, by treatment with N-bromosuccinimide (NBS) and dibenzoyl peroxide in a suitable solvent, such as carbon tetrachloride. The corresponding compound of Formula (II) in which Y is chlorine may be prepared analogously.

The intermediate compound of Formula (II), wherein R 6 is aryl and Het is Y and hydroxy or bromine, represented respectively by Formulas (IIb1) and (Ilb2) below, may be prepared according to Reaction Scheme 5a below:

Scheme 4b

<formula> formula see original document page 33 </formula>

Scheme 5a

<formula> formula see original document page 33 </formula>

The intermediate compound of Formula (II) wherein R 6 is aryl and Y is hydroxy represented by Formula (IIa 2) below may be prepared by reacting a compound of Formula (Vila) with a compound of Formula (Vllb). ), according to Reaction Scheme 4b, below:

Scheme 5a

<formula> formula see original document page 33 </formula>

In stage (a), a compound of formula (VIII) is reacted with a Het-H compound, for example, using n-butyllithium in a suitable solvent such as tetrahydrofuran or Et20 to effect the introduction of the radical Het. . In stage (b), the conversion of the hydroxy radical to a bromophoric radical may be effected, for example, by treating the compound of formula (IIbI) with a brominating agent, such as phosphorus tribromide or aqueous hydrobromic acid, to a suitable solvent such as dichloromethane. The corresponding compound of formula (II) wherein Y is chlorine may be prepared in a similar manner.

The intermediate compound of formula (II) wherein R 6 is Het and Y is toluenesulfonyloxy or methanesulfonyloxy, represented below by RSO 2 O, said intermediate compound represented by formula (IIb 3) below, may be prepared according to Reaction Scheme 5b below:

Scheme 5b

<formula> formula see original document page 34 </formula>

Conversion of the hydroxy radical to the mesylate outosylate ester radical may be effected, for example, by treating compound (IIbI) with respectively methanesulfonyl chloride or p-toluenesulfonyl chloride in the presence of a base such as triethylamine. and in a suitable solvent, such as dichloromethane.

The intermediate compound of formula (IV) wherein R 3 is arylmethyl or Het-methyl represented by formula (IVa) below wherein R 3a is aryl or Het may be prepared by reaction of a compound of formula (X) with a compound of formula (XI) according to Reaction Scheme 6 below:

Scheme 6

<formula> formula see original document page 34 </formula> The reaction of the compound of formula (X) with the compound of formula (XI) is generally carried out using sodium cyanoborohydride in the presence of an acid such as acetic acid, in a suitable solvent, such as methanol.

Alternatively, the intermediate compound of formula (IX) may be prepared by reacting a compound of formula (XII) with a compound of formula (XIII) according to Reaction Scheme 7 below:

Scheme 7

<formula> formula see original document page 35 </formula>

In the compound of formula (XII) in the above Scheme, L is a suitable leaving group such as chlorine and the reaction is generally carried out in the presence of a base such as potassium carbonate or sodium carbonate in the presence of a Suitable solvent, such as acetonitrile, dimethylformamide, N-methylpyrrolidone or diglyme.

The compound of formula (Ia) wherein R2 is pyrrolidine, represented by formula (Ia4), may be prepared by reaction of a compound of formula (XIV), wherein R2a is halo, for example chlorine, with pyrrolidine, according to with Reaction Scheme 8 below:

Scheme 8

<formula> formula see original document page 35 </formula>

Starting materials of formula (XIV) may be prepared in a manner analogous to that described for the preparation of compounds of formula (I), as shown in Scheme 1.

Compounds of formula (I) wherein R 1 is halo, for example bromine, may be converted to the corresponding compounds of formula (I) wherein R 1 is alkyl, for example methyl, by treatment with a suitable alkylating agent such as CH3B (OH) 2 or (CH3) 4 Sn, in the presence of Pd (PPh3) 4 in a suitable solvent, such as toluene or 1,2-dimethoxyethane (DME). Similarly, compounds of formula (I) wherein R 1 is halo, for example bromine, may be converted to the corresponding compounds of formula (I) wherein R 1 is pyridyl by treatment with 3- (1,3,2-dioxaborinan-2 -yl) -pyridine in the presence of Pd (PPh3) 4 and a base such as sodium carbonate in a suitable solvent such as DME.

Compounds of formula (Ib) may be prepared analogously to that described above for compounds of formula (Ia).

The compounds of Formulas (Ia) or (Ib) may be converted to their corresponding N-oxides in conventional manner, for example by treatment with 3-chloroperbenzoic acid, in a suitable solvent, such as dichloromethane.

It is evident that in the foregoing and subsequent reactions the reaction products may be isolated from the reaction medium and, if necessary, further purified according to generally known methodologies such as extraction, crystallization and chromatography. It is further evident that reaction products which exist in more than one enantiomeric form may be isolated from their mixture by known techniques, in particular preparatory chromatography such as preparative HPLC. Typically, the compounds of Formulas (Ia) or (Ib) may be separated into their isomeric forms.

The following Examples illustrate the present invention without any limitation thereof.

Experimental Part

Hereafter, "DME" is defined as 1,2-dimethoxyethane, "NBS" is defined as N-bromosuccinimide, "DMF" is defined as N, N-dimethylformamide, "THF" is defined as tetrahydrofuran, "DIPE" is defined as diidopropyl ether , "BTEAC" is defined as benzyltriethyl ammonium chloride, "EDCI" is defined as 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide.HCI, "HOBT" is defined as 1-hydroxybenztriazole, "DIAD" is defined as diisopropylazodicarboxylate and "NCO polymerlab" is defined as methylisocyanate-polystyrene.

A. Preparation of Intermediate Compounds

Example A1

a) Preparation of Intermediate 1

<formula> formula see original document page 37 </formula>

A mixture of 5-bromo-1H-indol-2,3-dione (0.066 mol) in 3N NaOH (150 mL) was stirred at 80 ° C for 30 minutes, then brought to room temperature and compound was added. 1,3-diphenyl-1-propanone (0.066 mol), the mixture being reheated to 80 ° C overnight, then cooled and acidified to umpH 5 with acetic acid. The precipitate was filtered off, washed with water and isopropyl ether and dried. Yield> 15 g of Intermediate 1 (55%).

b) Preparation of Intermediate 2

<formula> formula see original document page 37 </formula>

A mixture of intermediate 1 (15 g) in diphenyl ether (150mL) was stirred at 300 ° C overnight. The resulting mixture was purified by silica gel column chromatography (eluent: cyclohexane: 100). Pure fractions were collected and the solvent was evaporated. Production: 3.0 g of Intermediate 2 (22%).

c) Preparation of Intermediate 3

<formula> formula see original document page 37 </formula>

A mixture of intermediate 2 (0.0027 mol), 1-bromo-2,5-pyrolidinedione (0.0027 mol) and dibenzoyl peroxide (0.00005) in CCl 4 (10mL) was stirred and refluxed for 1 hour then poured into water and extracted with CH 2 Cl 2. The organic layer was separated, dried (Mg-SO 4), filtered, and the solvent evaporated. Yield: 1 g of Intermediate 3 (80%).

Example A2

a) Preparation of Intermediate 4

<formula> formula see original document page 38 </formula>

Benzene propanoyl chloride (0.488 mol) was added at room temperature to a solution of 4-bromobenzenamine (0.407 mol) in Et 3 N (70 mL) and CH 2 Cl 2 (700 mL), and the mixture was stirred at room temperature overnight. The mixture was poured into water and concentrated with NH 4 OH, then extracted with CH 2 Cl 2. The organic layer was dried (MgSO 4), filtered and the solvent was evaporated. The residue was crystallized from diethyl ether. The residue (119.67 g) was taken up in CH 2 Cl 2 and washed with 1 H HCl. The organic layer was dried (MgSO 4), filtered and the solvent was evaporated. Yield: 107.67 from Intermediate 4 (87%).

b) Preparation of Intermediate 5

<formula> formula see original document page 38 </formula>

The reaction was performed twice. Then, POCl 3 (1.225 mol) was added dropwise at 10 ° C in DMF (0.525 mol). Intermediate 4 (0.175 mol) was added at room temperature. The mixture was stirred overnight at 80 ° C, poured out on ice and extracted with CH 2 Cl 2. The organic layer was dried (MgSO 4), filtered and the solvent was evaporated. The product was used without further purification. Yield: 77.62 g of Intermediate 5 (67%).

c) Preparation of Intermediate 6

<formula> formula see original document page 38 </formula> A mixture of intermediate 5 (0.233 mol) in 30% CH3ONa in CH3OH (222.32 mL) and CH3OH (776 mL) was stirred and refluxed for overnight then poured out on ice and extracted with CH 2 Cl 2. The organic layer was separated, dried (MgSO 4), filtered, and the solvent evaporated. The residue was purified by silica gel column chromatography (eluent: CH 2 Cl 2 / cyclohexane, 20/80, and then 100/0; 20-45 μτη). The pure fractions were collected and the solvent was evaporated. Yield: 25 g of Intermediate6 (33%).

d) Preparation of Intermediate 7

<formula> formula see original document page 39 </formula>

A mixture of intermediate 6 (0.03 mol), 1-bromo-2,5-pyrrolidinedione (0.03 mol) and dibenzoyl peroxide (0.1 g) in CCl 4 (100 mL) was stirred and refluxed for One hour later, 10% K 2 CO 3 was added and the mixture was extracted with CH 2 Cl 2. The organic layer was separated, dried (MgSO 4), filtered, and the solvent evaporated. Yield: 12.2 g of Intermediate 7 (98%).

Example A3

Intermediate Preparation 8

<formula> formula see original document page 39 </formula>

A mixture of intermediate 6-bromo-3- (bromo-phenyl-methyl) -2-chloro-quinoline (prepared analogously to E-example A2d) (0.0036 mol), N, N-dimethyl-N '- (phenylmethyl) -1,2-ethanediamine (0.0036 mol) and K 2 CO 3 (0.0036 mol) in CH 3 CN (20 mL) was stirred at 80 ° C for 12 hours. The solvent was evaporated.The mixture was extracted with CH 2 Cl 2 / H 2 O. The organic layer was separated, dried (MgSO 4) filtered, and the solvent evaporated.The residue (2.3 g) was purified by column chromatography over silica gel (eluent: CH 2 Cl 2 / CH 3 OH, 98/2; 70-200 μπι) Desired fraction was collected and solvent was evaporated Yield: 0.4 g of Intermediate 8.

Example A4

a) Preparation of Intermediate 9

<formula> formula see original document page 40 </formula>

A mixture of 6-bromo-2-chloroquinoline (0.06 mol) in 30% CH 3 OH in CH 3 OH (70 mL) and CH 3 OH (140 mL) was stirred and refluxed overnight then poured into water and extracted with CH 2 Cl 2. The organic layer was separated, dried (MgSO 4), filtered, and the solvent evaporated. The residue (12.6 g) was purified by silica gel column chromatography (eluent: CH 2 Cl 2 / cyclohexane, 40/60; 15-35 μιη). The desired fraction was collected and the solvent was evaporated. Yield: 7.5 g of Intermediate 9.

b) Preparation of Intermediate 34

<formula> formula see original document page 40 </formula>

1.6M n-BuLi (0.03 mol) was added dropwise at a temperature between -20 ° C and -10 ° C to a solution of 2,2,6,6-tetramethylpiperidine (0.03 mol) in THF (90 mL) under a stream of nitrogen. The mixture was stirred at -20 ° C for 20 minutes, then cooled to -70 ° C. A solution of intermediate 9 (0.025 mol) in THF (39.6mL) was added dropwise. The mixture was stirred at -70 ° C for 1 hour. Then a solution of 2-fluorobenzaldehyde (0.03 mol) in THF (11.1 mL) was added dropwise. The mixture was stirred at -70 ° C for 3 hours and 30 minutes, then brought to room temperature, stirred at room temperature overnight, poured into water and extracted with EtOAc. The organic layer was washed with saturated NaCl, dried (MgSO 4), filtered and the solvent was evaporated. Yield: 9.96 g. This fraction was purified by column chromatography on silica gel (eluent gradient: cyclohexane / CH 2 Cl 2, 50/50 at 100/0; 15-40μητι). Two fractions were collected and the solvent was evaporated. Yield: 2.52 g of fraction A and 0.75 g of fraction 2. A third fraction was obtained by washing the column with CH 3 OH. The solvent was evaporated. Yield: 4.10 g of Intermediate 34 (45%).

Example A5

a) Preparation of Intermediate 10

<formula> formula see original document page 41 </formula>

POCl 3 (327 mL) was slowly added under a temperature of 5 ° C to DMF (120 mL). After complete addition, N- (4-methylphenyl) benzenopropanamide (0.501 mol) was added. The mixture was stirred at 80 ° C overnight then brought to room temperature and poured into ice. Then EtOac was added. The mixture was stirred for 1 hour while ice was added and then extracted with EtOAc. The organic layer was separated, washed with water, dried (MgSO4), filtered and the solvent was evaporated. Yield: 182.2 g of Intermediate 10.

b) Preparation of Intermediate 11

<formula> formula see original document page 41 </formula>

A mixture of intermediate 10 (0.0112 mol), phenylboronic acid (0.034 mol), Pd (PPh3) 4 (0.0011 mol) and 2M Na2 CO3 (0.056 mol) in DME (50 mL) was stirred at room temperature. 90 ° C, poured into water and extracted with CH 2 Cl 2. The organic layer was separated, dried (MgSO 4), filtered and the solvent was evaporated. The residue was crystallized from DIPE. The precipitate was filtered off and dried. Yield: 1 g (29%). This fraction was purified by silica gel column chromatography (eluent: cyclohexane / EtOAc, 90/10; 15-0 μπι). Pure fractions were collected and the solvent was evaporated. Yield: 2 g of Intermediate 11 (58%).

c) Preparation of Intermediate 12

<formula> formula see original document page 42 </formula>

A mixture of intermediate 11 (0.0088 mol) and NBS (0.0098 mol) in 1,2-dichloroethane (50 mL) was stirred and refluxed for 3 hours, poured into water and extracted with CH 2 Cl 2. The organic layer was separated, dried (MgSO 4), filtered and the solvent was evaporated. Production: 3.6 g of Intermediate 12.

Example A6

a) Preparation of Intermediate 13

<formula> formula see original document page 42 </formula>

Lithium hydroxide and water (0.0035 mol) were added to a mixture of final compound 146 (prepared according to B1a) (0.0018 mol) in THF (10 mL) and H2O (10 mL). The mixture was stirred at 60 ° C overnight. The THF was evaporated and 3N HCl was added. The precipitate was filtered off and dried. Yield: 1 g of Intermediate 13 (100%).

b) Preparation of Intermediate 14 Intermediate 14 was prepared analogously to Intermediate 13, but starting from final compound 131 (prepared according to B2.a). Production: Intermediate 14 (86%).

c) Preparation of Intermediate 15

<formula> formula see original document page 43 </formula>

A mixture of final compound 145 (prepared according to B2.c) (0.0008 mol) and LiOH, H2O (0.0026 mol) in THF (8 mL) and H2O (2 mL) was stirred at room temperature for 12 hours. then stirred at 60 ° C for 12 hours and poured into water. 5N HCl was added until the pH was set to 5. The mixture was extracted with CH 2 Cl 2. The organic layer was separated, dried (MgSO 4), filtered and the solvent was evaporated. Yield: 0.45 g of Intermediate 15 (97%).

d) Preparation of Intermediate 16

<formula> formula see original document page 43 </formula>

A mixture of final compound 137 (prepared according to B2.b) (0.0069 mol) and LiOH, H 2 O (0.0143 mol) in THF (20 mL) and H 2 O (20 mL) was stirred at room temperature for 12 hours, then stirred at 60 ° C for 24 hours. The THF was evaporated. The residue was taken up in H2 O / 3N HCl. The mixture was extracted with CH 2 Cl 2. The organic layer was separated, dried (MgSO 4), filtered and the solvent was evaporated. Yield: 3 g of Intermediate 16 (56%).

e) Preparation of Intermediate 17

B1.b) (0.0007 mol) and LiOH, H 2 O (0.0023 mol) in THF (10 mL) and H 2 O (10 mL) were stirred at room temperature for 12 hours, then poured into water and 3N HCl was added. The mixture was extracted with CH 2 Cl 2. The organic layer was separated, dried (MgSO 4), filtered and the solvent was evaporated.

Yield: 0.3 g of Intermediate 17.

f) Preparation of Intermediate 18

A mixture of final compound 151 (prepared according to B2.d) (0.0038 mol) and LiÒH, H2O (0.0077 mol) in H2O (20 ml) and THF (20 ml) was stirred at room temperature for 4 days. H 2 O and EtOAc was added. 3N NaOH was added. The organic layer was washed with saturated NaCl, dried (MgSO 4), filtered and the solvent was evaporated. Yield: 1.6g of the intermediate 18 (90%).

g) Preparation of Intermediate 37 A mixture of final compound 130 (prepared according to B2.h) (0.0015 mol) and LiOH, H 2 O (0.0045 mol) in THF (8 mL) and H 2 O (8 mL) was stirred at room temperature. 65 ° C for 24 hours, then cooled to room temperature. 3N HCl was added. The mixture was evaporated to dryness. Yield: 0.85 g of Intermediate 37 (100%).

Example A7

a) Preparation of Intermediate 19

<formula> formula see original document page 45 </formula>

A mixture of intermediate 6 (prepared according to A2.c) (0.0076 mol) and CuCN (0.028 mol) in DMF (25 mL) was stirred and refluxed for 16 hours, then cooled to room temperature and dried. poured into ice water. The precipitate was filtered, taken up in H2 O / ethylenediamine and extracted with CH2 Cl2. The organic layer was washed with saturated NaCl, dried (MgSO 4), filtered and the solvent was evaporated. The mixture was filtered over silica gel (eluent: CH 2 Cl 2). The mixture was evaporated to dryness. Yield: 1.1 g of Intermediate 19 (53%).

b) Preparation of Intermediate 20

<formula> formula see original document page 45 </formula>

A mixture of intermediate 19 (0.0066 mol), NBS (0.0066 mol) and dibenzoyl peroxide (0.0003 mol) in 1,2-dichloroethane (30 mL) was stirred at 80 ° C for 3 hours, then cooled to room temperature. H 2 O and CH 2 Cl 2 were added. The organic layer was washed with dry H 2 O 1 (filtered MgSO 4 and the solvent was evaporated. The residue (3.5 g) was purified by column chromatography over silica gel (eluent: cyclohexane / EtOAc 92/8; 15 -40 μητι) Pure fractions were collected and the solvent was evaporated Yield: 1.9 g of Intermediate 20 (81%).

Example A8

a) Preparation of Intermediate 21

<formula> formula see original document page 46 </formula>

A mixture of 2-quinoline carboxaldehyde (0.0019 mol), ethylglycine ester hydrochloride (0.002 mol) and NaBH3CN (0.0028 mol) in CH3OH (1mL) and CH3COOH (20 mL) was stirred at room temperature for 2 hours. 3 hours, poured into H 2 O and 10% K 2 CO 3 and extracted with CH 2 Cl 2 / CH 3 OH. The organic layer was separated, dried (MgSO 4), filtered and the solvent was evaporated.

The residue was purified by silica gel column chromatography (eluent: CH 2 Cl 2 / CH 3 OH / NH 4 OH 98/20 / 0.1; 15-40 μηη). Two pure fractions were collected and the solvent was evaporated. Yield: 1.7 g of Intermediate 21 (37%).

b) Preparation of Intermediate 27

<formula> formula see original document page 46 </formula>

Sodium cyanoborohydride (0.0334 mol) was added portionwise to a mixture of 5-quinoline carboxaldehyde (0.0223 mol), deethyl ester glycinic hydrochloride (0.0245 mol) and acetic acid (0.5 mL) in methanol (80 mL) at 0 ° C. The mixture was stirred for 4 hours at room temperature, then poured into 10% K 2 CO 3 and extracted with CH 2 Cl 2. The organic layer was dried over magnesium sulfate, filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH 2 Cl 2 / MeOH / NH 4 OH 97.5 / 2.5 / 0.1). Pure fractions were collected and the solvent was evaporated. Yield: 2.3 g of Intermediate 27 (43%).

Example A9

a) Preparation of Intermediate 22 <formula> formula see original document page 47 </formula>

1.6M n-BuLi in hexane (0.0103 mol) was added at -70 ° C to a solution of 3-bromopyridine (0.0103 mol) in diethyl ether (20 mL) under a stream of nitrogen. . The mixture was brought to -45 ° C, then cooled back to -70 ° C. A solution of 2-phenyl-3-quinoline carboxaldehyde (0.0008 mol) in THF (20 mL) was added. The mixture was stirred at -70 ° C to room temperature for 2 hours. Then water was added and the mixture was extracted with EtOAc. The organic layer was washed with saturated NaCl, dried (MgSO4), filtered and the solvent was evaporated. The residue was taken up in diethyl ether. The mixture was filtered, washed with diethyl ether and dried at 50 ° C under vacuum. Yield: 2.1 g of Intermediate 22 (79%).

b) Preparation of Intermediate 23

<formula> formula see original document page 47 </formula>

A mixture of intermediate 22 (0.0046 mol) in PBr3 (3 mL) etoluene (45 mL) was stirred and refluxed for one and a half hours, then cooled to room temperature. The precipitate was filtered off, washed with diethyl ether and dried at 60 ° C under vacuum. Yield: 2.4 g Intermediate 23 (> 100%) (melting point: 161 ° C).

Example A10

a) Preparation of Intermediate 24 <formula> formula see original document page 48 </formula>

A mixture of intermediate 5 (prepared according to A2.b) (0.009 mol) in 6N HCl (50 mL) was stirred and refluxed for night. The precipitate was filtered, washed with water, then with DIPE and dried.Production: 2.8 g of Intermediate 24.

Intermediate Preparation 25

<formula> formula see original document page 48 </formula>

A mixture of intermediate 24 (0.0089 mol), ICH3 (0.026 mol) and BTEAC (0.0044 mol) in NaOH (40 mL) and THF (30 mL) was stirred at room temperature overnight. , water was added. The mixture was extracted with EtOAc. The organic layer was separated, dried (Mg-SO 4), filtered and the solvent was evaporated. Yield: 1.5 g of Intermediate 25 (79%).

c) Preparation of Intermediate 26

<formula> formula see original document page 48 </formula>

A mixture of intermediate 25 (0.0043 mol) and NBS (0.0048 mol) in 1,2-dichloroethane (25 mL) was stirred and refluxed for 3 hours then poured into water. The organic layer was separated, dried (MgSO 4), filtered and the solvent was evaporated. Yield: 2 g of Intermediate 26.

Example A11 <formula> formula see original document page 49 </formula>

Phenol (0.066 mol) was added portionwise to a mixture of 60% NaH (0.069 mol) in 1,4-dioxane (200 mL) and DMF (80 mL), then intermediate 5 (prepared according to A2.b). was added and the suspension was heated under reflux for 20 hours. The mixture was cooled and poured into 10% K 2 CO 3 and extracted with CH 2 Cl 2. The organic layer was dried over magnesium sulfate, filtered and the solvent was evaporated. The residue was purified by silica gel column chromatography (eluent: cyclohexane / CH 2 Cl 2: 70/30). Pure fractions were collected and the solvent was evaporated. Yield: 7.3 g of Intermediate 28 (57%) (melting point: 111 ° C).

b) Intermediate Preparation 29

<formula> formula see original document page 49 </formula>

A mixture of intermediate 28 (0.0026 mol), NBS (0.0028 mol) and dibenzoyl peroxide (0.00005 mol) was stirred at 80 ° C for 3 hours, then poured into water and extracted with CH 2 Cl 2. The organic layer was separated, dried (MgSO 4), filtered and the solvent was evaporated. Yield: 1.3 g of Intermediate 29 (100%) (melting point: 110 ° C).

Example A12

Preparation of Intermediate 30 A mixture of 3,5-difluorobenzylamine (4.2 mmols), ethyl chloroacetate (4.2 mmols) and potassium carbonate (4.2 mmols) in acetonitrile (7 mL) was stirred at room temperature. 80 ° C for 18 hours. The mixture was cooled and poured into water and extracted with CH 2 Cl 2. The organic layer was dried over magnesium sulfate, filtered and the solvent was evaporated. Yield: 0.58 g of Intermediate 30 (60%).

Example A13

a) Preparation of Intermediate 31

A mixture of 4-bromoaniline (0.011 mol), benzylmalonic acid (0.011 mol) and phosphorus oxychloride (10 mL) was heated for 5 hours at 80 ° C and then evaporated to dryness. The residue was taken up in water and basified CH 2 Cl 2, extracted with CH 2 Cl 2, dried over magnesium sulfate, filtered and the solvent evaporated. Yield: 2.48 g of Intermediate 31 (62%).

b) Preparation of Intermediate 32

A mixture of intermediate 31 (0.011 mol) and sodium methoxide (30% in MeOH, 0.011 mol) in MeOH was heated under reflux for 3 hours and then cooled to room temperature and poured into ice / water. The precipitate was filtered off, dried and purified by silica gel column chromatography (eluent: cyclohexane / CH 2 Cl 2: 70/30). The pure fractions were collected and the solvent was evaporated. Yield: 1.6 g of Intermediate32 (40%).

c) Preparation of Intermediate 33

<formula> formula see original document page 51 </formula>

A mixture of intermediate 32 (0.0053 mol) and di-benzoyl peroxide (0.0002 mol) in trifluorotoluene (31 mL) was stirred at 80 ° C for 5 hours, then cooled to room temperature. Then, water and CH 2 Cl 2 were added. The organic layer was washed with water, dried (MgSO 4), filtered and the solvent was evaporated. The residue (2.68 g) was crystallized from diethyl ether. The precipitate was filtered off and dried. Production: 2.4 g of Intermediate 33 (85%) (melting point: 117 ° C).

Example A14

a) Preparation of Intermediate 35

<formula> formula see original document page 51 </formula>

1.6M n-BuLi in hexane (0.0257 mol) was added at -70 ° C to a solution of benzofuran (0.0257 mol) in THF (30 mL) under a stream of nitrogen. The mixture was stirred at -70 ° C for 3 hours. A solution of 2-phenyl-3-quinoline-3-carbaldehyde (prepared in accordance with the teachings of US Patent Application No.2004 / 009976, the entire contents of which are incorporated herein) (0.0129 mol) in THF (30 mL) was added. The mixture was stirred at -70 ° C for 3 hours, then poured into ice at -20 ° C and extracted with EtOAc. The organic layer was washed with saturated aqueous NaCl solution, dried (MgSO4), filtered and the solvent was evaporated. The residue was crystallized from diethyl ether. The precipitate was filtered off and dried. Yield: 3.75 g of Intermediate 35 (83%) (melting point: 184 ° C).

b) Preparation of Intermediate 36

<formula> formula see original document page 52 </formula>

PBr3 (0.0006 mol) was added dropwise at room temperature to a solution of intermediate 35 (0.0005 mol) in CH 2 CF 3 (5 mL). The mixture was stirred at room temperature for 30 minutes and evaporated to dryness. Production: Intermediate 36.

B. Preparation of Final Compounds

Example B1

a) Preparation of Compound 146

<formula> formula see original document page 52 </formula>

A mixture of intermediate 3 (prepared according to A1, c) (0.0004 mol), N- (phenylmethyl) glycine ethyl ester (0.0008 mol) and K2CO3 (0.0013mol) in CH3CN (6 mL) was stirred at 80 ° C overnight. Then water was added and the mixture was extracted with CH 2 Cl 2. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated. The residue (0.3 g) was purified by Kromasil column chromatography (eluent: cyclohexane / EtOAc, 90/10; 10 μιη). Pure fractions were collected and the solvent was evaporated. Yield: 0.165 g of final compound 146 (66%).

b) Preparation of Compound 150 <formula> formula see original document page 53 </formula>

A mixture of the final compound 146 (prepared according to B1.a) (0.0007 mol), tetracis (triphenylphosphino) palladium (0.00007 mol) and (CH3) 4Sn (0.0014 mol) in toluene (8 mL) was stirred and refluxed for 2 hours, poured into water and extracted with CH 2 Cl 2. The organic layer was dried, dried (MgSO 4), filtered and the solvent was evaporated. The residue was purified by silica gel column chromatography (eluent: cyclohexane / EtOAc, 90/10; 15-40 μητι). The pure fractions were collected and the solvent was evaporated. Yield: 0.109 g of final compound 150 (31%).

c) Preparation of Compound 152

<formula> formula see original document page 53 </formula>

A mixture of the final compound 146 (prepared according to B1.a) (0.53 mmol), Pd (PPh3) 4 (0.053 mmol), 1,3-propanediol pyridine boronic acid cyclic ester (0.0016 mol) and . 2M aqueous sodium carbonate (0.0027 mol) in dimethylglycol (7 mL) was stirred at 90 ° C, then poured into water and extracted with CH 2 Cl 2. The organic layer was separated. It was dried over magnesium sulfate, filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH 2 Cl 2 Z MeOH: 95/5). The pure fractions were collected and the solvent was evaporated. Yield: 62 mg of final compound 152 (21%).

Example B2

Preparation of Compound 131 <formula> formula see original document page 54 </formula>

A mixture of intermediate 7 (prepared according to A2.d) (0.24 mmol), ethyl ester sarcosine hydrochloride (0.24 mmol) and K 2 COg (0.24 mmol) in CH 3 CN (5 mL) was stirred at room temperature. 80 ° C for 18 hours. The mixture was cooled and poured into water, then extracted with CH 2 Cl 2. The organic layer was separated, dried over MgSO 4, filtered and the solvent was evaporated. The residue was crystallized from diisopropyl ether. The precipitate was filtered off and dried. Yield: final compound 137 (100%).

b) Preparation of Compound 137

<formula> formula see original document page 54 </formula>

A mixture of intermediate 7 (prepared according to A2.d) (0.004 mol), N- (phenylmethyl) glycine ethyl ester (0.0009) and K2CO3 (0.0014 mol) in CH3CN (8 mL) was stirred at 80 ° C overnight. The mixture was poured into water, then extracted with CH 2 Cl 2. The organic layer was separated, dried (MgSO 4), filtered and the solvent was evaporated. The residue (0.3 g) was purified by silica gel column chromatography (eluent: α-cloexane / EtOAc, 90/10; 15-40 μιη). The pure fractions were collected and the solvent was evaporated. Yield: 0.054 g of final compound 137 (21%).

c) Preparation of Compound 145

<formula> formula see original document page 54 </formula>

A mixture of intermediate 7 (prepared according to A2.d) (0.0098 mol), intermediate 27 (prepared according to A8.b) (0.0098 mol) and K 2 CO 3 (0.0108 mol) in CH 3 CN (80 mL) was stirred at 80 ° C for 12 hours. The mixture was extracted with CH 2 Cl 2 / H 2 O. The organic layer was separated, dried (MgSO 4), filtered and the solvent was evaporated. The residue (5.4 g) was purified twice by silica gel column chromatography (eluent gradient: CH 2 Cl 2 / CH 3 OH, 98/2 to 99/1; 15-40 μηι). The pure fractions were collected and the solvent was evaporated. Yield: 0.66 g of compostofinal 145 (12%) (melting point: 96 ° C).

d) Preparation of Compound 151

<formula> formula see original document page 55 </formula>

A mixture of intermediate 20 (prepared according to A7.b) (0.0053 mol), N- (phenylmethyl) glycine ethyl ester (0.008 mol) and K2CO3 (0.008 mol) in CH3CN (20 mL) was stirred and subjected. The reflux for 18 hours was then cooled to room temperature and poured into water and EtOAc. The organic layer was washed with saturated NaCl, dried (MgSO 4), filtered and the solvent was evaporated. The residue (3 g) was crystallized from diethyl ether. The precipitate was filtered off and dried. Yield: 1.85 g of final compound 151 (74%) (melting point: 148 ° C).

A solution of intermediate 23 (prepared according to A9.b) (0.0037 mol) in N- (phenylmethyl) glycine ethyl ester (7 mL) was stirred at 125 ° C for 6 hours, then cooled to room temperature. room temperature, poured into water and extracted with EtOAc. The organic layer was washed with water, then saturated aqueous NaCl solution, dried (MgSO 4), filtered and the solvent was evaporated. Yield: 0.4 g. This fraction was purified by silica gel column chromatography (eluent: cyclohexene / EtOAc, 60/40; 15-40 μπι). Two fractions were collected and the solvent was evaporated. Yield: 2.65 g of fraction 1 and 0.35 g of fraction 2 (19%). Fraction 1 was taken up in CH2 Cl2 / NCO polymerlab. The mixture was stirred at room temperature for 2 hours, then filtered and the filtrate was evaporated. Production: 0.32 g of final compound 129 (18%).

f) Preparation of Compound 153

<formula> formula see original document page 56 </formula>

A mixture of intermediate 26 (prepared according to A10.c) (0.0012 mol), N-methylglycine ethyl ester hydrochloride (0.0019 mol) and K2CO3 (0.0024 mol) in CH3CN (15 mL) was stirred at room temperature. 80 ° C for 6 hours. The solvent was evaporated to dryness. The residue was taken up in H 2 O and CH 2 Cl 2. The organic layer was separated, dried (MgSO 4), filtered and the solvent was evaporated. Yield: 0.46 g of final compound 153.

q) Preparation of Compound 132

<formula> formula see original document page 56 </formula>

A mixture of intermediate 33 (prepared according to A13.c) (0.0027 mol), N-methylglycine ethyl ester hydrochloride (0.0027 mol) and K2CO3 (0.004 mol) in CH3CN (12 mL) was stirred and refluxed. for 23 hours. Then, N-methylglycine ethyl ester hydrochloride (1 equivalent) and K2CO3 (1 equivalent) were added. The mixture was stirred and refluxed for 24 hours, then cooled to room temperature, poured into water and EtOAc. The organic layer was washed with saturated NaCl, dried (MgSO 4), filtered and the solvent was evaporated. The residue (1.15 g) was purified by silica gel column chromatography (eluent: cyclohexane / EtOAc, 95/5; 15-40 μιτ). The desired fraction was collected and the solvent was evaporated. Yield: 0.68 g of final compound 132 (52%).

h) Preparation of Compound 130

<formula> formula see original document page 57 </formula>

A mixture of intermediate 36 (prepared according to A14.b) (0.0056 mol), N- (phenylmethyl) glycine ethyl ester (0.0171 mol) and K2CO3 (0.0171 mol) in CH3CN (50 mL) was stirred and refluxed for 18 hours, poured into water and extracted with CH 2 Cl 2. The organic layer was washed with saturated NaCl, dried (MgSO 4), filtered and the solvent was evaporated. The residue (5 g) was purified by silica gel column chromatography (eluent: cyclohexane / EtOAc, 90/10). Pure fractions were collected and the solvent was evaporated. Yield: 0.79 g of final compound 130 (27%).

i) Preparation of Compound 143

<formula> formula see original document page 57 </formula>

The final compound 143 was prepared in an analogous manner to Example B2.c, starting from intermediate 21.

i) Preparation of Compound 148 <formula> formula see original document page 58 </formula>

The final compound 148 was prepared in an analogous manner to Example B2.c, starting from intermediate 29.

k) Preparation of Compound 141

<formula> formula see original document page 58 </formula>

The final compound 141 was prepared analogously to Example B2.c, starting from intermediate 30.

Example B3

a) Preparation of Compound 53

<formula> formula see original document page 58 </formula>

A mixture of intermediate 13 (prepared according to A6.a) (0.0003 mol), diethylamine (0.0005 mol), EDCI (0.0005 mol), HOBT (0.0005 mol) and Et3N (0.0005 mol) ) in CH 2 Cl 2 / THF (8 mL) was stirred at room temperature for 3 hours, poured into water and extracted with CH 2 Cl 2. The organic layer was separated, dried (MgSO 4), filtered and the solvent was evaporated. The residue (0.2 g) was crystallized from DLP. The precipitate was filtered and dried. Yield: 0.053 g of final compound 53 (melting point: 110 ° C).

b) Preparation of Compound 30 <formula> formula see original document page 59 </formula>

A mixture of intermediate 1

<formula> formula see original document page 59 </formula>

{benzyl - [(6-bromo-2-phenoxy-quinolin-3-yl) -phenyl-methyl] amino} acetic acid} (prepared in a manner analogous to Example A6.c) (0.0002 mol), hydrochloride N-methyl-2-propanamine (0.0003 mol), EDCI (0.0004 mol) and HOBT (0.0004 mol) in CH 2 Cl 2 (3 mL) and THF (3 mL) were stirred at room temperature for 12 hours. then poured into water and CH 2 Cl 2. The organic layer was separated, dried (MgSO 4), filtered and the solvent was evaporated. The residue (0.25 g) was purified by Kromasil column chromatography (15 μιτι). The pure fractions were collected and the solvent was evaporated. Yield: final compound 30 (37%).

c) Preparation of Compound 3

<formula> formula see original document page 59 </formula>

A mixture of intermediate 14 (prepared according to A6.b) (0.0002 mol), methylamine hydrochloride (0.0002 mol), EDCI (0.0003 mol) and HOBT (0.0003 mol) in CH2 Cl2 (2 mL ), THF (2 mL) and triethylamine (0.1 mL) was stirred at room temperature for 12 hours, then poured into water and extracted with CH 2 Cl 2. The organic layer was separated, dried (MgSO 4), filtered and the solvent was evaporated. The residue (0.15 g) was purified by Kromasil column chromatography (eluent: CH 2 Cl 2, 100, para CH 2 Cl 2 ZCH 3 OH, 90/10; 5 μηη). Pure fractions were collected and the solvent was evaporated. Yield: 0.063 g of final compound 3 (62%) (melting point: 190 ° C).

d) Preparation of Compound 41

<formula> formula see original document page 60 </formula>

A mixture of intermediate 17 (prepared according to A6.e) (0.0008 mol), N-methyl-2-propanamine (0.001 mol), EDCI (0.0012 mol) and HOBT (0.0012 mol) in CH2 Cl2 (5 mL) and THF (5 mL) was stirred at room temperature for 12 hours, then poured into water and CH 2 Cl 2, and further stirred for 5 minutes. The organic layer was separated, dried (MgSO 4), filtered and the solvent was evaporated. The residue (0.42 g) was purified by Kromasil column chromatography (eluent: CH 2 Cl 2 / CH 3 OH, 99/1; 5 µιτι). Two fractions were collected and the solvent was evaporated. Yield: 0.14 g of fraction t and 0.064 g of fraction 2. Fraction 1 was crystallized from DI-PE / diethyl ether. The precipitate was filtered off and dried. Yield: 0.138 g of final compound 41 (31%) (melting point: 126 ° C).

e) Preparation of Compound 45

<formula> formula see original document page 60 </formula>

A mixture of intermediate 17 (prepared according to A6.e) (0.0002 mol), dimethylamine (0.0003 mol), Et3N (0.0004 mol), EDCI (0.0003 mol) and HOBT (0.0003 mol) ) in CH 2 Cl 2 (2 mL) and THF (2 mL) was stirred at room temperature for 12 hours, then poured into water and extracted with CH 2 Cl 2. The organic layer was separated, dried (MgSO 4), filtered and the solvent was evaporated. The residue (0.1 g) was purified by Kromasil column chromatography (eluent: CH 2 Cl 2 ZCH 3 OH, 99/1; 10 μηι). Two fractions were collected and the solvent was evaporated. Yield: 0.056 g of fraction A and 0.1 g of fraction Β. Fraction A was taken up in diethyl ether. The mixture was evaporated. Yield: 0.055 g of final compound 45 (52%).

f) Preparation of Compound 36

A mixture of intermediate 37 (prepared according to A6.g) (0.0004 mol), N-methyl-2-propanamine (0.0004 mol), EDCI (0.0006 mol) and HOBT (0.0006 mol) in CH 2 Cl 2 (5 mL) and THF (5 mL) was stirred at room temperature for 3 hours and water was added. The mixture was extracted with CH 2 Cl 2 and then filtered. The organic layer was separated, dried (MgSO 4), filtered and the solvent was evaporated. The residue (0.12 g) was purified by Kromasil column chromatography (eluent gradient: CH 2 Cl 2 / CH 3 OH 100/0 to 98/2; 5 μπι). Pure fractions were collected and the solvent was evaporated.

Yield: 0.073 g of final compound 36 (33%).

Example B4

a) Preparation of Compound 104

<formula> formula see original document page 61 </formula>

A mixture of intermediate 16 (prepared according to A6.d) (0.0006 mol), 1-methylpiperazine (0.0009 mol), EDCI (0.0009 mol) and HOBT (0.0009 mol) in CH2 Cl2 (8 mL) and THF (8 mL) was stirred at room temperature for 1 hour, then poured into water and extracted with CH 2 Cl 2.

The organic layer was separated, dried (MgSO 4), filtered and the solvent was evaporated. The residue (0.4 g) was purified by Kro-masil column chromatography (eluent: CH 2 Cl 2 ZCH 3 OH, 95/5; 5 μηι). Pure fractions were collected and the solvent was evaporated. The residue was crystallized from DI-PE / diethyl ether. The precipitate was filtered off and dried. Yield: 0.107 g of final compound 104 (31%) (melting point: 152 ° C).

b) Preparation of Compound 69

<formula> formula see original document page 62 </formula>

A mixture of intermediate 17 (prepared according to A6.e) (0.0002 mol), 4-methylpiperazine (0.0002 mol), EDCI (0.0003 mol) and HOBT (0.0003 mol) in CH2 Cl2 ( 3 mL) and THF (3 mL) was stirred at room temperature for 12 hours, then evaporated to dryness. The residue was taken up in EtOH. The precipitate was filtered off and dried. Yield: 0.3 g. This fraction was purified by Kromasil column chromatography (eluent: CH 2 Cl 2 / CH 3 OH / NH 4 OH 95/5 / 0.1; 10 μηι). Two fractions were collected and the solvent was evaporated. Yield: 0.082 g of fraction A (34%) and 0.03 g of fraction Β. Fraction A was purified by Kromasil column chromatography (eluent: CH 2 Cl 2 / CH 3 OH / NH 4 OH 98/2 / 0.2; 3.5 μηι). Pure fractions were collected and the solvent was evaporated. Yield: 0.05 g of final compound 69 (21%).

c) Preparation of Compound 72

<formula> formula see original document page 62 </formula>

A mixture of intermediate 17 (prepared according to A6.e) (0.0021 mol), N-methylpiperazine (0.0003 mol), EDCI (0.0033 mol) and HOBT (0.0033 mol) in CH2 Cl2 (2 mL) and THF (2 mL) was stirred at room temperature for 12 hours, then poured into water and extracted with CH 2 Cl 2. The organic layer was separated, dried (MgSO 4), filtered and the solvent was evaporated. The residue (0.1 g) was purified by Kromasil column chromatography (eluent: CH 2 Cl 2 / CH 3 OH / NH 4 OH 99/4 / 0.1; 10 μηι). Two fractions were collected and the solvent was evaporated. Yield: 0.06 g of fraction A and 0.007 g of fraction Β. Fraction A was dissolved in diethyl ether. The mixture was evaporated. Yield: 0.056 g of final compound 72 (48.5%).

A mixture of intermediate 17 (prepared according to A6.e) (0.0008 mol), piperidine (0.001 mol), EDCI (0.0012 mol) and HOBT (0.0012 mol) in CH 2 Cl 2 (5 mL) and THF ( 5 mL) was stirred at room temperature for 12 hours, then poured into water and extracted with CH 2 Cl 2. The organic layer was separated, dried (MgSO 4), filtered and the solvent was evaporated. The residue (0.46 g) was purified by Kro-masil column chromatography (eluent: CH 2 Cl 2 / CH 3 OH, 99/1; 5 μιτι). Two fractions were collected and the solvent was evaporated. Yield: 0.094 g of fraction A and 0.048 g of fractionΒ. Fraction A was crystallized from DIPE / diethyl ether. The precipitate was filtered and dried. Yield: 0.094 g of final compound 66 (21%) (m.p .: 78 ° C).

e) Preparation of Compound 114

<formula> formula see original document page 63 </formula>

A mixture of intermediate 15 (prepared according to A6.c) (0.0001 mol), N-methylpiperazine (0.0002 mol), EDCI (0.0002 mol) and HOBT (0.0002 mol) in CH2 Cl2 (3 mL) and THF (3 mL) was stirred at room temperature for 12 hours, then poured into H2 O / CH2 Cl2. The organic layer was separated, dried (MgSO 4), filtered and the solvent was evaporated. The residue (0.11 g) was purified by Kromasil column chromatography (eluent: CH 2 Cl 2 / CH 3 OH 95/5; 5 μηι). The pure fractions were collected and the solvent was evaporated. The residue was dried with diethyl ether. Yield: 0.062 g of final compound 114 (55%).

f) Preparation of Compound 122

<formula> formula see original document page 64 </formula>

A mixture of intermediate 18 (prepared according to A6.f) (0.0004 mol), pyrrolidine (0.0006 mol), EDCI (0.0006 mol) and HOBT (0.0006 mol) in CH2 Cl2 (4 mL) and THF (4 mL) was stirred at room temperature for 18 hours, water and CH 2 Cl 2 were added, the mixture was filtered and the filtrate was evaporated. The residue was purified by Kromasil column chromatography (eluent: CH 2 Cl 2 / CH 3 OH, 95/5; 10 μιη). Pure fractions were collected and the solvent was evaporated. The residue (0.14 g) was crystallized from diethyl ether. The precipitate was filtered and dried at 50 ° C under vacuum. Yield: 0.068 g of final compound 122 (32%) (melting point: 161 ° C).

q) Preparation of Compound 70

<formula> formula see original document page 64 </formula>

A mixture of intermediate 17 (prepared according to A6.e) (0.0008 mol), thiomorpholine (0.001 mol), EDCI (0.0012 mol) and HOBT (0.0012 mol) in CH2 Cl2 (5 mL) and THF ( 5 mL) was stirred at room temperature for 12 hours, then poured into water and CH 2 Cl 2, and further stirred for 5 minutes. The organic layer was separated, dried (MgSO 4), filtered and the solvent was evaporated. The residue (0.48 g) was purified by Kromasil column chromatography (eluent: GH2Cl2ZCH3OH1 99/1; 5 μηι). The purple fractions were collected and the solvent was evaporated. The residue (0.117 g) was crystallized from DIPE / diethyl ether. The precipitate was filtered and dried. Yield: 0.029 g of final compound 70 (25%) (melting point: 144 ° C).

Example B5

Preparation of Compound 59A mixture of final compound 105 (prepared analogously).

A mixture of final compound 105 (prepared analogously to Example B4.a) (0.0002 mol), methylboronic acid (0.0005 mol), Pd (PPh3) 4 (0.00002) and 2M Na2 CO3 (0 0.011 mol) in DME (2.9 mL) was stirred at 90 ° C for 6 hours, then cooled to room temperature and water added. The mixture was extracted with CH 2 Cl 2. The organic layer was separated, dried (MgSO 4), filtered and the solvent was evaporated, yielding 0.238 g. The fraction was purified by silica gel column chromatography (eluent: CH 2 Cl 2 / CH 3 OH, 99/1; 10 μηι). Two fractions were collected and the solvent was evaporated. Yield: 0.08 g of fraction A and 0.06 g of fraction Β. Fraction B was crystallized from DIPE. The precipitate was filtered off and dried. Yield: 0.047 g of final compound 59 (33%) (melting point: 126 ° C).

Example B6

Preparation of Compound 154

<formula> formula see original document page 67 </formula>

3-Chlorobenzenecarboperoxoic acid (0.0005 mL) was added at a temperature of 5 ° C to a solution of final compound 105 (prepared analogously to Example B4.a) (0.0005 mol) in CH 2 Cl (7 mL). The mixture was stirred at room temperature for 24 hours, then poured into water and extracted with CH 2 Cl 2. The organic layer was washed with water, dried (MgSO 4), filtered and the solvent was evaporated. The residue (0.3 g) was purified by Kromasil column chromatography (eluent: CH 2 Cl 2 / CH 3 OH, 100/0 a98 / 2; 5 μπι). Two fractions were collected and the solvent was evaporated. Production: 0.07 g of fraction A and 0.013 g of final compound 154 (4%).

Example B7

Preparation of Compound 29

<formula> formula see original document page 66 </formula>

A mixture of intermediate 8 (prepared according to A3.a) (0.0002 mol) in pyrrolidine (0.5 mL) was stirred at 140 ° C for 12 hours. The residue was purified by Kromasil column chromatography (eluent: CH 2 Cl 2 / CH 3 OH / NH 4 OH, 98/2 / 0.1; 10 μηη). Pure fractions were collected and the solvent was evaporated. The residue was taken up in dry diethyl ether. Yield: 0.08 g of final compound 29 (58%).

Example B8

a) Preparation of Compound 51

<formula> formula see original document page 66 </formula>

A mixture of intermediate 3 (prepared according to A1.c) (0.0006 mol), N, N-dimethyl-N '- (phenylmethyl) -1,2-ethanediamine (0.0009 mol) and K2CO3 (0.0009 mol) in CH 3 CN (6 mL) was stirred at 80 ° C overnight, poured into water and extracted with EtOAc. The organic layer was separated, dried (MgSO 4), filtered and the solvent was evaporated. The residue (0.44 g) was purified by column chromatography over silica gel (eluent: CH 2 Cl 2 / CH 3 OH / NH 4 OH 98/2 / 0.5; 20 μηι). Pure fractions were collected and the solvent was evaporated. Yield: 0.17 g of final compound 51 (47%).

b) Preparation of Compound 18

<formula> formula see original document page 67 </formula>

A mixture of intermediate 7 (prepared according to A2.d) (0.0012 mol), N, N-dimethyl-N'-phenyl-1,2-ethanediamine (0.0018 mol) and K2CO3 (0.0018 mol) ) in CH 3 CN (10 mL) was stirred at 80 ° C overnight, poured out on ice and extracted with CH 2 Cl 2. The organic layer was separated, dried (MgSO 4), filtered and the solvent was evaporated. The residue (0.86g) was purified by Kromasil column chromatography (eluent: CH 2 Cl 2 / CH 3 OH / NH 4 OH 97/3 / 0.1; 15-40 μηι). Two fractions were collected and the solvent was evaporated. Yield: 0.64 g of fraction A and 0.01 g of fractionΒ. Fraction A was crystallized from DIPE. The precipitate was filtered off and dried. Yield: 0.03 g of final compound 18 (melting point: 120 ° C).

Example B9

Preparation of Compound 22

<formula> formula see original document page 67 </formula>

DIAD (0.0027 mol) was added dropwise at a temperature of 0 ° C to a mixture of intermediate 34 (prepared according to A4.b) (0.0014 mol), N, N-dimethyl-N '- (phenylmethyl ) -1,2-ethanediamine (0.0027 mol) ePPh3 (0.0027 mol) in THF (15 mL) under a stream of nitrogen. The mixture was stirred at room temperature overnight, poured into water and extracted with CH 2 Cl 2. The organic layer was separated, dried (MgSO 4), filtered and the solvent was evaporated. The residue (2.6 g) was purified by silica gel column chromatography (eluent: CH 2 Cl 2 / CH 3 OH / NH 4 OH 97/3 / 0.1; 15-40μηι). Pure fractions were collected and the solvent was evaporated. The residue (0.086 g) was purified by Kromasil column chromatography (eluent: CH 2 Cl 2 / CH 3 OH / NH 4 OH 98/2 / 0.1; 10 μηι). Pure fractions were collected and the solvent was evaporated. Yield: 0.05 g of final compound 22 (7%).

Example B10

a) Preparation of Compound 20

<formula> formula see original document page 68 </formula>

A mixture of intermediate 7 (prepared according to A2.d) (0.0013 mol) and N, N-dimethyl-N '- (2-methoxyphenyl) -1,2-ethanediamine (0.0026 mol) was stirred at room temperature. 90 ° C for 2 hours, then taken up in eCH2 Cl2 water. The organic layer was separated, dried (MgSO 4), filtered and the solvent was evaporated. The residue (0.5 g) was purified by Kromasil column chromatography (eluent: CH 2 Cl 2 / CH 3 OH / NH 4 OH 95/5 / 0.1; 10 μηι). The purple fractions were collected and the solvent was evaporated. The residue (0.84 g) was dissolved in CH 3 COCH 3 and converted to the ethanedioic acid salt. The precipitate was filtered off and dried. Yield: 0.099 g of final compound 20 (18%) (melting point: 142 ° C).

b) Preparation of Compound 37

<formula> formula see original document page 68 </formula>

A mixture of intermediate 12 (prepared according to A5.c) (0.0013 mol) and Ν, Ν, Ν'-trimethyl-1,2-ethanediamine (0.0026 mol) was stirred at 90 ° C for 2 hours, then taken in water and CH 2 Cl 2. The organic layer was separated, dried (MgSO 4 filtered and the solvent was evaporated. The residue (0.5 g) was purified by Kroma-sil column chromatography (eluent: CH 2 Cl 2 / CH 3 OH / NH 4 OH 95/5 / 0.1; 10 μπι) Pure fractions were collected and the solvent was evaporated The residue (0.84 g) was dissolved in CH3 COCH3 and converted to the ethanedioic acid salt The precipitate was filtered and dried Yield: 0.099 g of final compound 37 (18%) (m.p .: 142 ° C).

Example B11

a) Preparation of Compound 83

A mixture of intermediate 14 (prepared according to A6.b) (0.17 mmol), 4-methylpiperidine (0.255 mmol), 1-hydroxybenzotriazole (0.255 mmol) and 1- (3-dimethylaminopropyl) -3- Ethylcarbodiimide (0.03g, 0.255 mmol) in THF / CH 2 Cl 2 (1: 1.4 mL) was stirred at room temperature for 12 hours. The mixture was poured into water and the organic layer was separated. The product was purified by silica gel chromatography (Kromasil5 μιτι, 250x20 mm; CH 2 Cl 2: 100 to CH 2 Cl 2 / MeOH 90:10). The pure fractions were collected and the solvent was evaporated. Yield: final compound 83 (58%).

b) Preparation of Compound 47

A mixture of intermediate 17 (prepared according to A6.e) (0.15 mmol), diethylamine (0.225 mmol), 1-hydroxybenzotriazole (0.225 mmol) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.225 mmol) ) in THF / CH 2 Cl 2 (1: 1.4 mL) was stirred at room temperature for 12 hours. The mixture was poured into water and the organic layer was separated. The product was purified by silica gel chromatography (Kromasil 5 μιη, 250x20 mm; CH 2 Cl 2: 100 to CH 2 Cl 2 / MeOH, 95: 5). Pure fractions were collected and the solvent was evaporated. Yield: final compound 47 (44%).

c) Preparation of Compound 2

<formula> formula see original document page 70 </formula>

A mixture of intermediate 7 (prepared according to A2.d) (0.25 mmol), N, N-diethyl-N'-methylethylenediamine (0.25 mmol) and depotassium carbonate (0.25 mmol) in acetonitrile (5 mL) was stirred at 80 ° C for 18 hours. The mixture was poured into water and the organic layer was separated. The product was purified by silica gel chromatography (Kro-masil 5 μιη, 250x20 mm; CH 2 Cl 2: 100 to CH 2 Cl 2 / MeOH 95: 5). The purple fractions were collected and the solvent was evaporated. Yield: final compound 2 (69%).

Tables 1-6 list compounds that were prepared analogously to the above Examples (ExempkrN5). <table> table see original document page 71 </column> </row> <table> <table> table see original document page 72 </column></row><table> <table> table see original document page 73 </column> </row> <table> <table> table see original document page 74 </column> </row> <table > <table> table see original document page 75 </column> </row> <table> <table> table see original document page 76 </column> </row> <table> <table> table see original document page 77 </column></row><table> <table> table see original document page 78 </column> </row> <table> <table> table see original document page 79 </column> </row> <table > <table> table see original document page 80 </column> </row> <table> <table> table see original document page 81 </column> </row> <table> <table> table see original document page 82 </column></row><table> <table> table see original document page 83 </column> </row> <table> <table> table see original document page 84 </column> </ ro w> <table> <table> table see original document page 85 </column> </row> <table> <table> table see original document page 86 </column> </row> <table> <table> table see original document page 87 </column> </row> <table> <table> table see original document page 88 </column> </row> <table> <table> table see original document page 89 </column> </ row> <table> <table> table see original document page 90 </column> </row> <table> <table> table see original document page 91 </column> </row> <table> <table> table see original document page 92 </column> </row> <table> <table> table see original document page 93 </column> </row> <table> C. Analytical Data

For a given number of compounds, melting point or LCMS data were recorded.

1. Melting Points

If possible, melting points (or ranges) were obtained from a Leica VMHB Koffler database. Melting points are uncorrected.

2. LCMS Conditions

Method 1:

The LCMS Method was performed (positive mode electrospray ionization, 100 to 900 amu scan mode) on a Kromasil C18 column (Interchim, Montluçon, France), 5 μηι, 4.6 χ 150 mm), with flow rate. 1 ml / min. Two mobile phases (mobile phase A: 30% 6.5 mM ammonium acetate + 40% acetonitrile + 30% formic acid (2 mL / L); mobile phase B: 100% acetonitrile) were used to process a gradient condition. from 100% A for 1 minute to 100% B in 4 minutes, 100% B for 5 minutes to 100% A in 3 minutes and rebalancing with 100% A for 2 minutes).

Method 2:

The LCMS Method was performed (electrospray ionization in positive mode and negative (pulsed) mode on a KromasilC18 column (Interchim, Montluçon, France), 5 μιτι, 4.6 χ 100 mm), with a flow rate of 0.8mL. /minute. Two mobile phases (mobile phase A: 35% 6.5 mM ammonium acetate + 30% acetonitrile + 35% formic acid (2mL / L); mobile phase B: 100% acetonitrile) were used to process a gradient condition of 100% A for 1 minute to 100% B in 4 minutes, 100% B at a flow rate of 1.2 mL / minute for 4 minutes to 100% A at a flow rate of 0.8 mL / 3 minutes and rebalance with 100% A for 1.5 minutes).

Method 3:

The LCMS Method was performed (electrospray ionization in positive mode and negative (pulsed) mode, scanning mode 100 to 1000 amu) on a Sunfire C18 column (Waters, Millford, USA), 3.5μιη, 4,6 χ 100 mm), with a flow rate of 0.8 mL / min. Two mobile phases were used (mobile phase A: 35% 6.5 mM ammonium acetate + 30% ace-tonitrile + 35% formic acid (2 mL / L); mobile phase B: 100% acetonitrile). -la) to process a gradient condition of 100% A for 1 minute to 100% B in 4 minutes, 100% B at a flow rate of 1.2 mL / minute for 4 minutes to 100% A at a 0.8 mL / min in 3 minutes and rebalance with 100% A for 1.5 minutes).

Method 4:

The LCMS Method was performed (electrospray ionization in positive mode, 100 to 900 amu scan mode) on a Xterra MS C18 column (Waters, Millford, USA), 3.5 μπι, 3.9 χ 150 mm) with a flow rate of 1 mL / min. Two mobile phases (mobile phase A: 85% 6.5 mM ammonium acetate + 15% acetonitrile; mobile phase B: 20% 6.5 mM ammonium acetate + 80% acetonitrile) were used to process a grain. 100% A for 3 minutes to 100% B in 5 minutes, 100% B for 6 minutes to 100% A in 3 minutes and rebalance with 100% Apor 3 minutes).

Table 7: LCMS Source Peak

<table> table see original document page 95 </column> </row> <table> <table> table see original document page 96 </column> </row> <table> <table> table see original document page 97 < / column> </row> <table> <table> table see original document page 98 </column> </row> <table>

D. Pharmacological Examples

D.1. In vitro Method for Testing Compounds against M. tuberculosis

Sterile 96-well plastic flat microtiter plates were filled with 100 μL of Mid-dlebrook broth medium (1 time). Subsequently, stock solutions (10 χ the final test concentration) of the compounds were added in 25 μL volumes to a series of duplicate wells in column 2 to allow evaluation of their effects on bacterial growth. Five serial dilutions were made directly into the microtiter plates of columns 2 through 11 using a custom robot system (Zymark Corp., Hopkinton, MA). Pipette tips were modified after every 3 dilutions to minimize pipetting errors with highly hydrophobic compounds. Untreated inoculum (lane 1) and non-inoculum (lane 12) control samples were included in each microtiter plate. Approximately 5000 CFU porcity of Mycobacterium tuberculosis (strain H37RV) in a volume of 100 μl. in Middlebrook broth medium (1 time), were added to rows A to H except in column 12. The same volume of non-inoculum broth medium was added to column 12 in rows A to H. The cultures were incubated at a temperature of .37 ° C. ° C for 7 days in a humidified atmosphere (incubator with open air valve and continuous ventilation). One day before the end of incubation, 6 days after inoculation, Resazurin (1: 5) was added to all wells in a volume of 20 μL and the plates were incubated for an additional 24 hours at 37 ° C. On day 7, bacterial growth was fluorometrically quantified.

Fluorescence was read on a computer-controlled fluorometer (Spectramax Gemini EM, Molecular Devices) at an excitation wavelength of 530 nm and an emission wavelength of 590 nm. The percentage growth inhibition obtained by the compounds was calculated according to standard methods and expressed as PIC50 values. The results are shown in Table 8.

D.2. In vitro Method for Testing Compounds for Antibacterial Activity against M. smeamatis Strains. ATCC607.

Sterile 96-well plastic flat microtiter plates were filled with 180 μL of sterile deionized water supplemented with 0.25% BSA. Subsequently, stock solutions (7.8 χ the final test concentration) of the compounds were added in 45 μL volumes to a series of duplicate wells in column 2 to allow evaluation of their effects on bacterial growth. 5 serial dilutions (45 μL to 180 μL) were made directly onto the microtiter plates of columns 2 to 11 using a custom robot system (Zymark Corp., Hopkinton, MA). Pipette tips were modified after every 3 dilutions to minimize pipetting errors with high hydrophobicity compounds. Control samples not treated with inoculum (lane 1) and without inoculum (lane 12) were included in each microtiter plate. Approximately 250 CFU per bacterial inoculum well in a volume of 100 μL in the Mueller-Hinton broth medium (2.8 times) were added to the AaH rows except for column 12. The same volume Broth medium without inoculum was added to column 12 in AaH rows. Cultures were incubated at 37 ° C for 48 hours in a humidified 5% CO 2 atmosphere (open air incubator and continuous ventilation). At the end of incubation, 2 days after inoculation, bacterial growth was quantified fluorometrically. In addition, A-Iamar Blue (10 times) was added to all wells in a volume of 20 μL and the plates were incubated for a further 2 hours at 50 ° C.

Fluorescence was read on a computer-controlled fluorometer (Cytofluor, Biosearch) at an excitation wavelength of 530 nm and an emission wavelength of 590 nm (gain of 30). Growth inhibition percentage obtained by the compounds was calculated according to standard methods and expressed as pICso values. The results are shown in Table 8.

Table 8 - Results of an in vitro selection of compounds according to

<table> table see original document page 100 </column> </row> <table> <table> table see original document page 101 </column> </row> <table> <table> table see original document page 102 < / column> </row> <table> <table> table see original document page 103 </column> </row> <table> <table> table see original document page 104 </column> </row> <table> <table> table see original document page 105 </column> </row> <table>

D.3. In vitro Method for Testing Compounds for Antibacterial Activity against Several Non-Mycobacterial Strains.

Preparation of Bacterial Suspensions for Sensitivity Testing

The bacteria used in this study were grown overnight in flasks containing 100 ml Mueller-Hinton broth (Becton Dic-kinson, Catalog No. 275730) in sterile deionized water with shaking at 37 ° C. Stocks (0.5 mL / tube) were stored at -70 ° C until use. Bacterial titrations were performed in microtiter plates to detect the TCID50, where TCID50 represents the addition that provides the emergence of bacterial growth in 50% of inoculated cultures.

In general, an inoculum level of approximately 100 TCID50 was used for the sensitivity test.

Antibacterial Sensitivity Test: Determination of ICgn

Microtiter Plate Assay

Sterile 96-well plastic flat microtiter plates were filled with 180 μι of sterile deionized water supplemented with 0.25% BSA. Subsequently, stock solutions (7.8 χ the final test concentration) of the compounds were added in 45 μL volumes in column 2, 5 serial dilutions (45 μΙ in 180 μL) were made directly into the microtiter plates of columns 2 to 11, Control samples not treated with inoculum (column 1) and without inoculum (column 12) were included in each microtiter plate. Depending on the bacterial type, approximately 10 to 60 CFU per bacterial inoculum well (100 TCID50) in a volume of 100 μl. in Muel-read-Hinton broth medium (2.8 times) were added to rows AaH except in column 12. The same volume of broth medium without inoculum was added to column 12 in rows A to H. incubated at 37 ° C for 24 hours in a normal atmosphere (continuous eventylating open air incubator). At the end of incubation, one day after inoculation, bacterial growth was fluorometrically quantified. Resazurin (0.6 mg / mL) was then added in a volume of 20 μΙ_ at all wells 3 hours after inoculation and the plates were again incubated overnight. A color change from blue to pink indicated the growth of the bacteria. The fluorescence was read on a computer controlled fluorometer (Cytofluor Biosearch) at an excitation wavelength of 530 nm and an emission wavelength of 590 nm. The% growth inhibition obtained by the compounds was calculated according to standard methods. The ICgo (expressed in μρ / ηιΙ-) was defined as 90% of the bacterial growth inhibitory concentration. The results are shown in Table 9.

Water Dilution Method.

MICgg values (minimum concentration to obtain 99% inhibition of bacterial growth) can be determined by medianizing the agar dilution method according to NCCLS * standards, where the medium used included Mueller-Hinton agar.

* Standard Institute of Clinical Laboratory (2005). Methods for diluting Antimicrobial Sensitivity Tests for aerobically growing bacteria; approved standard - 6a. Edition.

Elimination Tests Over Time

The bactericidal or bacteriostatic activity of the compounds may be determined in a time-course elimination assay using the broth microdilution method *. In an over time elimination assay for methicillin-resistant Staphylococcus aureus and S. aureus (MRSA), the starting inoculum of S. aureus and MRSA is 106 CFU / mL in Mueller-Hinton broth. Antibacterial compounds are used at the concentration of 0.1 to 10 fold MIC (i.e. IC90 as determined in the microtiter plate assay). Cavities that do not receive the antibacterial agent constitute the control of culture growth. Plaques containing the microorganism and test compounds are incubated at 37 ° C. After 0, 4, 24 and 48 hours of incubation, samples are removed for viable counts by serial dilution (10 "1 to 10" 6) in sterile PBS and plating (200 μΙ_) on Mueller-Hinton agar. The plates are incubated at 37 ° C for 24 hours and the number of colonies is determined. Elimination curves can be constructed by plotting log10 CFU / mL versus time. A bactericidal effect is commonly defined as a 3-log reduction in the number of CFU per mL when compared to untreated inoculum. Potential drug maintenance effect is removed by serial dilution and colony counting at the highest dilution used for plating. * Zurenko G.E. et al. "In vitro activities of U-100592 and U-100766, noveloxazolidinone antibacterial agents." Antimicrob. Chemother Agents. 40, 839-845 (1996).

ATP Cellular Level Determination

In order to analyze the change in total ATP cell concentration (using the Roche ATP1 Bioluminescence Kit) the assays are performed by growing a culture from a S. aureus stock (ATCC29213) in 100 ml Mueller-Hinton flasks and incubating in a 24 hour shaking incubator at 37 ° C (300rpm). OD405 nm is measured and CFU / mL is calculated. Dilute the cultures to 1 χ 106 CFU / mL (final ATP measurement concentration: 1 χ 105CFU / 100 μl per well) and add test compound from 0.1 to 10 times the MIC (ie IC90 as determined). microtiter plate assay). These tubes are incubated for 0, 30 and 60 minutes at 300 rpm and temperature of 37 ° C. 0.6 ml of the bacterial suspension of the pressure buffer tubes is used and added to new 2 ml eppendorf tubes. 0.6 ml of Cell Iise Reagent (Kit Roche), vortex at full speed and incubation for 5 minutes at room temperature are added. It is then cooled on ice. The luminometer is then allowed to warm up to 30 ° C (Luminoskan Ascent Labsystems, with injector). One column (= 6 wells) is filled with 100 μΙ of the same sample. 100 µl of Luciferase reagent is added to each well using the injection system. Measure luminescence for 1 second. <table> table see original document page 108 </column> </row> <table> <table> table see original document page 109 </column> </row> <table> BSU 43639 means Bacillus subtilis (ATCC43639); ECO 25922 means Escherichia eoli (ATCC25922); EFA 14506 means Enterocoeeusfaeealis (ATCC14506); EFA 29212 means Enterocoeeus faeealis (ATCC29212); LMO 49594 means Listeria monoeytogenes (ATCC49594);

PAE 27853 means Pseudomonas aeruginosa (ATCC27853); SMU 33402 means Streptoeoeeus mutans (ATCC33402); SPN 6305 means Streptoeoceus pneumoniae (ATCC6305); SPY 8668 means Streptoeoeeus pyogens (ATCC8668); STA 43300 means Staphyloeoeeus aureus (ATCC43300); STA 25923 means Staphyloeoeeus aureus (ATCC25923);

STA 29213 means Staphyloeoeeus aureus (ATCC29213); STA RMETH stands for methicillin-resistant Staphyloeoeeus aureus (MRSA) (a clinical isolate from the University of Antwerp). ATCC stands for American-type tissue culture.

Claims (14)

1. A compound, characterized in that it has either General Formula (1a) or General Formula (1b), a pharmaceutically acceptable acid or base addition salt of the same, a quaternary amine thereof, a stereochemically isomeric form thereof, a tautomeric form thereof, an N-oxide form thereof or a prodrug thereof, wherein: - ρ is an integer equal to 0, 1, 2, 3 or 4 - q is an integer equal to 1, 2 or 3 - Z is a radical selected from the formulas: <formula> formula see original document page 111 </formula> - R1 is cyano, halo, alkyl, haloalkyl, hydroxy, alkyloxy, alkylthio, alkyloxyalkyl, alkylthioalkyl, arylalkyl, di (aryl) alkyl, aryl or Het; - R2 is hydrogen, alkyloxy, aryl, aryloxy, hydroxy, mercapto, alkyloxyoxy, mono or diylthio, (alkyl) amino, pyrrolidine or a radical of formula wherein Y is UH 2, O, t> NH or N-alkyl; - R 3 is alkyl, arylalkyl, aryl, mono- or di-alkylaminoalkyl, Het or Het-alkyl R4 and R51 each independently is hydrogen; alkyl, alkyloxyalkyl; arylalkyl; Hetalkyl; mono- or dialkylaminoalkyl; Het; ouarila; or - R4 and R5 together with the nitrogen atom to which they are attached form a radical selected from the group consisting of pyrrolidine, piperidino, piperazine, morpholine, 4-thiomorpholino, 2,3-dihydroisoindol-1-yl, thiazo-lidin-2-one. 3-yl, 1,2,3,6-tetrahydropyridyl, 1,4-diazacycloeptyl, 1-aza-4-oxacycloeptyl, -1,2,3,4-tetrahydroisoquinolin-2-yl, 2H-pyrrolyl, pyrrolinyl, pyrrolyl , imidazolidine, pyrazolidinyl, 2-imidazolinyl, 2-pyrazolinyl, imidazolyl, pyrazolyl, triazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl and triazinyl, optionally substituted by one or more substituents, each independently selected from haloalkyl, arylalkyl, hydroxy, alkyloxy, amino, mono- or dialkylamino, alkylthio, alkyloxyalkyl, alkylthioalkyl, aryl, pyridylor pyrimidinyl -R 6 is aryl or Het -R 7 is hydrogen, halo, alkyl, aryl or Het -R 8 is a radical saturated straight or branched chain hydrocarbon having from 1 to 6 carbon atoms, - R 9 is hydrogen or alkyl; - R 10 is oxo; and X is -CH 2 - or -C 0 - Alkyl is a straight chain or branched saturated hydrocarbon radical having from 1 to 6 carbon atoms; or is a cyclic saturated hydrocarbon radical having from 3 to 6 carbon atoms; or is a cyclic saturated hydrocarbon radical having from 3 to 6 carbon atoms attached to a straight or branched chain saturated hydrocarbon radical having from 1 to 6 carbon atoms; wherein each carbon atom may be optionally substituted by cyano, hydroxy, alkyloxy or oxo Aryl is a homocycle selected from phenyl, naphthyl, acenaphthyl or tetrahydronaphthyl, each optionally substituted by 1, 2 or 3 substituents, each substituent being independently selected from hydroxy halo, cyano, nitro, amino, mono- or dialkylamino, alkyl, haloalkyl, alkyloxy, carboxyl, alkyloxycarbonyl, aminocarbonyl, morpholinyl or mono- or dialkylaminocarbonyl; -Het is a monocyclic heterocyclic selected from N-phenoxypiperidinyl, piperidinyl pyrrole, pyrrolyl imidazolyl, furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl; or a bicyclic heterocyclic selected from quinolinyl, quinoxa-linyl, indolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzofuranyl, benzothienyl, 2,3-dihydrobenzo [1,4] dioxinyl orbenzo [1,3] dioxolyl; each monocyclic and bicyclic heterocyclyl being optionally substituted by 1, 2 or 3 substituents, each substituent being independently selected from halo, hydroxy, alkyl or alkyloxy: Halo is a substituent selected from fluorine, chlorine, bromine or iodine; e- Haloalkyl is a saturated or branched chain hydrocarbon radical having from 1 to 6 carbon atoms or a cyclic saturated hydrocarbon radical having from 3 to 6 carbon atoms or a cyclic saturated hydrocarbon radical having from 3 to 6 atoms carbon attached to a straight or branched chain saturated hydrocarbon having from 1 to 6 carbon atoms; wherein one or more carbon atoms are replaced by one or more halogen atoms. A compound according to claim 1, characterized in that: - ρ is 0 or 1; R1 is halo or alkyl; R2 is alkyloxy or aryl; R3 is aryl, arylalkyl or Hetalkyl; q is 1; R 4 and R 51 each independently represent alkyl or R 4 and R 5 together with the nitrogen atom to which they are attached form a 4-thiomorpholine, piperidino or pipe-razino radical substituted by alkyl or arylalkyl; R 6 is aryl optionally substituted by halo, or R 6 is benzofuranyl; R7 is hydrogen; and R 8 is straight chain or branched saturated hydrocarbon radical having 1 to 4 carbon atoms. A compound according to any one of claims 1 and 2, characterized in that ρ is 1; Z is a radical of formula (a); R1 is bromo or methyl; R 2 is methyloxy or phenyl; R3 is phenyl optionally substituted by methyloxy or benzyl; q is 1; R4 and R51 each represent methyl, ethyl or isopropyl, or R4 and R5 together with the nitrogen atom to which they are attached form a 4-thiomorpholino radical, a 4-methyl substituted piperidino radical or a radical benzyl substituted piperazine at position 4; R 6 is phenyl or benzofuranyl; and R7 is hydrogen. A compound according to claim 2, characterized in that ρ is 0 or 1; R1 is bromo or methyl; R 2 is methyloxy or phenyl; R3 is phenyl, benzyl or quinoline-5-ylmethyl; q is 1; R4 and R51 each represent ethyl or R4 and R5 together with the nitrogen atom to which they are attached form a methyl-substituted piperazine radical at position 4; R 6 is phenyl optionally substituted by fluorine at position 2; R7 is hydrogen; eR8 is ethyl. Compound according to Claim 1, characterized in that the compound is selected from: - 2- {benzyl - [(6-methyl-2-phenyl-quinolin-3-yl) -phenyl-methyl] -amino} -N- (4-methylpiperazin-1-yl) acetamide; N - [(6-bromo-2-methoxy-quinolin-3-yl) phenylmethyl] -N11 N'-dimethyl N-phenylethane-1,2-diamine; N-benzyl-N - [(6-bromo-2-phenyl-quinolin-3-yl) -phenyl-methyl] -N ', N-dimethyl-ethane- - 1,2-diamine; 2- {benzyl - [(6-methyl-2-phenyl-quinolin-3-yl) -phenyl-methyl] -amino} -1- (4-methyl-piperazin-1- 2) {[(6-bromo-2-methoxy-quinolin-3-yl) -phenyl-methyl] -quinolin-5-ylmethyl-amino} -1- (4-methyl-piperazin-1) 2- (benzyl - [(6-bromo-2-methoxy-quinolin-3-yl) -phenyl-methyl] -amino} -1- (4-methyl-piperazin-1-yl) N-benzyl-N - [(6-bromo-2-methoxy-quinolin-3-yl) - (2-fluoro-phenyl) -methyl] -N ', N'-dimethyl-ethane-1,2 {benzyl - [(6-bromo-2-methoxy-quinolin-3-yl) -phenyl-methyl] -amino} -acetic acid ethyl ester; and 2- {benzyl - [(6-methyl-2-phenyl-quinolin-3-yl) -phenyl-methyl] -amino} -1-piperidin-1-yl-ethanone; pharmaceutically acceptable base thereof, a quaternary amine thereof, a stereochemically isomeric form thereof, a tautomeric form thereof, an N-oxide form thereof or a prodrug thereof. A compound according to claim 1, characterized in that the compound is selected from: -2- {benzyl - [(6-methyl-2-phenyl-quinolin-3-yl) -phenyl-methyl] -amino} -1- (4-benzyl-piperazin-1-yl) -ethanone; -N - [(6-bromo-2-methoxy-quinolin-3-yl) -phenyl-methyl] -N- (2- methoxy-phenyl) -N ', N-dimethyl-ethane-1,2-diamine; -2- {benzyl - [(6-methyl-2-phenyl-quinolin-3-yl) -phenyl-methyl] -amino} -N, N-dimethyl acetamide; N-benzyl-N - [(6-bromo-2-phenyl-quinolin-3-yl) -phenyl-methyl] -N ', N'-dimethyl-ethane-1,2 -2- {benzyl - [(6-methyl-2-phenyl-quinolin-3-yl) -phenyl-methyl] -amino} -1- (4-methyl-piperidin-1-yl) -diamine; -2- {benzyl - [(6-methyl-2-phenyl-quinolin-3-yl) -phenyl-methyl] -amino} -N, N-diethyl-acetamide; -2- {benzyl - [(6 -bromo-2-phenyl-quinolin-3-yl) -phenyl-methyl] -amino} -N, N-dimethyl-acetamide; -2 - {[benzofuran-2-yl- (2-phenyl-quinolin-3-one) yl) -methyl] -benzyl-amino} -N-isopropyl-N-methyl-acetamide -2- {benzyl - [(6-methyl-2-phenyl-quinolin-3-yl) -phenyl-methyl] -amino } -1-thiomorpholin-4-yl-ethanone; and 2- {benzyl - [(6-methyl-2-phenyl-quinolin-3-yl) -phenyl-methyl] -amino} -N-isopropyl-N-methyl-acetamide; pharmaceutically acceptable base thereof, a quaternary amine thereof, a stereochemically isomeric form thereof, a tautomeric form thereof, an N-oxide form thereof or a prodrug thereof. A compound according to any one of claims 1 to 6, characterized in that it is intended for use as a medicament. Composition, characterized in that it comprises a pharmaceutically acceptable vehicle and, as active ingredient, a therapeutically effective amount of a compound as defined in any one of claims 1 to 6. Use of a compound as defined in any one of claims 1 to 6 or of a composition as defined in claim-8, characterized in that it is in the manufacture of a medicament for treating a bacterial infection. Use according to claim 9, characterized in that the bacterial infection is an infection with Staphylococci, Enterococ-ei or Streptoeoeei. Use according to claim 9, characterized in that the bacterial infection is a methicillin-resistant Staphyloeoeeus aureus (MRSA) 1 methicillin-resistant coagulase-negative staphylococci (MRCNS), penicillin-resistant Streptoeoeeus pneumoniae or Enteroeoceus faeeium resistant multiple. Use according to claim 9, characterized in that the bacterial infection is an infection with Staphyloeoeeus aureus or Streptoeoeeus pneumoniae. Use according to claim 12, characterized in that the bacterial infection is a methicillin resistant Staphyloeoeeus au-reus (MRSA) infection. Use of a compound as defined in any one of claims 1 to 6 or a composition as defined in claim-8, characterized in that it is in the manufacture of a medicament for treating a bacterial disease caused by Myeobaeterium tubereu-losis.